Source: s3://data.kl3m.ai/documents/govinfo/USCOURTS/USCOURTS-cand-3_14-cv-04741/USCOURTS-cand-3_14-cv-04741-18/pdf.json

Nature of Suit Code: 830
Nature of Suit: Patent
Cause of Action: 28:1331 Fed. Question

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UNITED STATES DISTRICT COURT

NORTHERN DISTRICT OF CALIFORNIA

AMGEN INC., et al.,

Plaintiffs,

v.

SANDOZ INC., et al.,

Defendants.

Case No. 14-cv-04741-RS 

ORDER CONSTRUING CLAIMS

I. INTRODUCTION

Amgen, Inc. and Sandoz Inc., Sandoz International GmbH, and Sandoz GmbH 

(collectively “Sandoz”) compete to develop, manufacture, promote, and sell biopharmaceutical 

products, including those used to facilitate stem-cell transplantation. Amgen holds two patents at 

issue in this action: U.S. Patent Nos. 6,162, 427 (“the ’427 Patent”) and 8,940,878 (“the ’878 

Patent”). Amgen accuses Sandoz of infringing those patents. The parties seek construction of ten 

terms pursuant to Markman v. Westview Instruments, Inc., 52 F.3d 967 (Fed. Cir. 1995) (en banc). 

For the reasons set forth below, the disputed terms are construed as follows.

II. BACKGROUND

In 2014, Amgen filed claims against Sandoz for infringement of the ’427 patent, 

“Combination of G-CSF with a Chemotherapeutic Agent for Stem Cell Mobilization.” Amgen 

objects to Sandoz’s efforts to market and sell ZARXIO®, a drug Amgen contends is biosimilar to 

its drug, NEUPOGEN®, which is commonly used to “treat[] the side effects of certain forms of 

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cancer therapy.” FAC ¶ 11. The active ingredient in both products is filgrastim, a synthetic 

version of human granulocyte colony stimulating factor (“G-CSF”). Amgen also accuses Sandoz 

of violating California’s unfair competition law (“UCL”). In response, Sandoz asserts numerous 

counterclaims for declaratory judgments of compliance with the Biosimilars Price Competition 

and Innovation Act (“BPCIA”), non-infringement, and patent invalidity. In March 2015, Sandoz 

obtained partial judgment in its favor with respect to the UCL claim and Sandoz’s claim for a 

declaratory judgment of compliance with the BPCIA pursuant to Federal Rule of Civil Procedure 

54(b). The parties jointly requested to stay these proceedings until the issuance of the Federal 

Circuit’s mandate. Dkt. No. 111 at 3.

Amgen then appealed to the Federal Circuit. During the pendency of the appeal, the 

Federal Circuit entered an injunction to prevent Sandoz from marketing, selling, or importing 

ZARXIO®. The Federal Circuit affirmed dismissal of the UCL claim, and affirmed in part and

reversed in part the order regarding the BPCIA. See Amgen Inc. v. Sandoz Inc., 794 F.3d 1347 

(Fed. Cir. 2015). Sandoz filed a petition for en banc review, which is still pending in the Federal 

Circuit.

Following the issuance of the Federal Circuit’s mandate, the parties agreed to lift the stay, 

and Amgen filed a First Amended Complaint, asserting one additional claim of patent 

infringement. Amgen now contends Sandoz employs a method of protein capture that infringes 

the ’878 patent, entitled “Capture Purification Processes for Proteins Expressed in a NonMammalian System.” 

III. LEGAL STANDARD

Claim construction is a question of law to be determined by the court. Markman, 52 F.3d 

at 979. “Ultimately, the interpretation to be given a term can only be determined and confirmed 

with a full understanding of what the inventors actually invented and intended to envelop with the 

claim.” Renishaw PLC v. Marposs Societa’ per Azioni, 158 F.3d 1243, 1250 (Fed. Cir. 1998). 

Accordingly, a claim should be construed in a manner that “most naturally aligns with the patent’s 

description of the invention.” 

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ORDER CONSTRUING CLAIMS

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The first step in claim construction is to look to the language of the claims themselves. “It 

is a ‘bedrock principle’ of patent law that ‘the claims of a patent define the invention to which the 

patentee is entitled the right to exclude.’” Phillips v. AWH Corp., 415 F.3d 1303, 1312 (Fed. Cir. 

2005) (quoting Innova/Pure Water, Inc. v. Safari Water Filtration Sys., Inc., 381 F.3d 1111, 1115 

(Fed. Cir. 2004)). A disputed claim term should be construed in a manner consistent with its 

“ordinary and customary meaning,” which is “the meaning that the term would have to a person of 

ordinary skill in the art in question at the time of the invention, i.e., as of the effective filing date 

of the patent application.” Phillips, 415 F.3d at 1312–13. The ordinary and customary meaning 

of a claim term may be determined solely by viewing the term within the context of the claim’s 

overall language. See id. at 1314 (“[T]he use of a term within the claim provides a firm basis for 

construing the term.”). Additionally, the use of the term in other claims may provide guidance 

regarding its proper construction. Id. (“Other claims of the patent in question, both asserted and 

unasserted, can also be valuable sources of enlightenment as to the meaning of a claim term.”).

A claim should also be construed in a manner that is consistent with the patent’s 

specification. See Markman, 52 F.3d at 979 (“Claims must be read in view of the specification, of 

which they are a part.”). Typically the specification is the best guide for construing the claims. 

See Phillips, 415 F.3d at 1315 (“The specification is . . . the primary basis for construing the 

claims.”); see also Vitronics Corp. v. Conceptronic, Inc., 90 F.3d 1576, 1582 (Fed. Cir. 1996) 

(“[T]he specification is always highly relevant to the claim construction analysis. Usually, it is 

dispositive; it is the single best guide to the meaning of a disputed term.”). In limited 

circumstances, the specification may be used to narrow the meaning of a claim term that otherwise 

would appear to be susceptible to a broader reading. See SciMed Life Sys., Inc. v. Advanced 

Cardiovascular Sys., Inc., 242 F.3d 1337, 1341 (Fed. Cir. 2001) (“Where the specification makes 

clear that the invention does not include a particular feature, that feature is deemed to be outside 

the reach of the claims of the patent, even though the language of the claims, read without 

reference to the specification, might be considered broad enough to encompass the feature in 

question.”); Phillips, 415 F.3d at 1316 (“[T]he specification may reveal an intentional disclaimer, 

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or disavowal, of claim scope by the inventor. In that instance as well, the inventor has dictated the 

correct claim scope, and the inventor’s intention, as expressed in the specification, is regarded as 

dispositive.”). Precedent forbids, however, a construction of claim terms that imposes limitations 

not found in the claims or supported by an unambiguous restriction in the specification or 

prosecution history. Laitram Corp. v. NEC Corp., 163 F.3d 1342, 1347 (Fed. Cir. 1998) (“[A] 

court may not import limitations from the written description into the claims.”); Comark 

Commc’ns., Inc. v. Harris Corp., 156 F.3d 1182, 1186 (Fed. Cir. 1998) (“[W]hile claims are to be 

interpreted in light of the specification, it does not follow that limitations from the specification 

may be read into the claims.” (internal quotation marks and alterations omitted)); SRI Int’l v. 

Matsushita Elec. Corp. of Am., 775 F.2d 1107, 1121 (Fed. Cir. 1985) (en banc) (“It is the claims

that measure the invention.”) (emphasis in original). A final source of intrinsic evidence is the 

prosecution record and any statements made by the patentee to the United States Patent and 

Trademark Office (“PTO”) regarding the scope of the invention. See Markman, 52 F.3d at 980.

Courts may also consider extrinsic evidence, such as expert testimony, dictionaries, or 

technical treatises, especially if such sources are “helpful in determining ‘the true meaning of 

language used in the patent claims.’” Phillips, 415 F.3d at 1318 (quoting Markman, 52 F.3d at 

980). Ultimately, while extrinsic evidence may aid the claim construction analysis, it cannot be 

used to contradict the plain and ordinary meaning of a claim term as defined within the intrinsic 

record. See Phillips, 415 F.3d at 1322–23.

IV. DISCUSSION

A. The ’427 Patent

Hematopoietic stem cells naturally occur in the human body and are capable of 

proliferation and differentiation into cells that comprise the blood and immune systems. In other 

words, they are blood-forming stem cells. 1 These cells self-renew and reside primarily in bone 

marrow.

 

1

In the interest of using plain language, this order uses the term “blood-forming stem cells” 

instead of “hematopoietic stem cells.”

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Peripheral stem cell transplantation is a process used to replace damaged blood-forming 

stem cells—the sort of cellular damage chemotherapy usually causes. Peripheral blood is the 

blood that circulates through the body. Before peripheral stem cell transplantation can occur, the 

doctor must collect blood-forming stem cells for later transplantation. Collection requires 

“mobilizing” stem cells in the bone marrow to move into the peripheral blood stream. Once the 

stem cells have mobilized, doctors collect them using a process called leukapheresis, which 

separates the stem cells from other types of blood cells. The collected cells are then set aside for 

later use. The more blood-forming stem cells in the blood stream, the fewer leukapheresis 

sessions the patient must undergo to collect enough cells for transplantation.

G-CSF is a protein that naturally occurs in the human body. Filgrastim is a pharmaceutical 

analog of human G-CSF constructed artificially in E. coli bacteria using recombinant DNA 

technology. Since the early 1990s, doctors and researchers have been using G-CSF in connection 

with chemotherapy to relieve the side effects of chemotherapy. G-CSF has also been used to 

facilitate mobilization of blood-forming stem cells from the bone marrow into the peripheral 

blood. 

After the stem-cell collection, the patient undergoes myeloablative radiation (bone marrow 

destruction) or myelotoxic chemotherapy (bone marrow suppression), which destroy bloodforming stem cells in the process. Once chemotherapy has been administered, the collected stem 

cells can be reintroduced into the bone marrow to allow for further production of new blood cells.

Both parties agree that the ’427 patent describes a method that requires administration of 

G-CSF before administration of a chemotherapeutic agent. The order of administration (G-CSF 

first, a chemotherapeutic agent second) is the allegedly novel component of the invention. At the 

time of the invention, a skilled artisan knew that administration of G-CSF alone, a 

chemotherapeutic agent alone, or a chemotherapeutic agent followed by G-CSF could mobilize 

blood-forming stem cells into the blood stream. The patentees purport to have reached the 

revolutionary conclusion that the structured administration of G-CSF first, followed by 

administration of a chemotherapeutic agent was the most efficient method of stem cell 

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mobilization. The patent claims to improve on the process of stem cell collection by following the 

specified order, which relieves patients of the need to attend multiple of leukapheresis sessions.

1. “hematopoietic stem cell mobilizing-effective amount of G-CSF”

The term “hematopoietic stem cell mobilizing-effective amount of G-CSF” appears in only 

claim 1, but is incorporated by reference into claims 2, 3, 4, and 6. Amgen would have the term 

construed to mean “an amount of G-CSF effective to mobilize hematopoietic stem cells,” whereas 

Sandoz contends the term is indefinite.

When evaluating whether a term is sufficiently definite, courts must analyze that question 

“from the viewpoint of a person skilled in the art at the time the patent was filed.” Nautilus, Inc. 

v. Biosig Instruments, Inc., 134 S. Ct. 2120, 2128 (2014) (emphasis, internal quotation marks, and 

alteration omitted). As noted, the claims “are to be read in light of the patent’s specification and 

prosecution history.” Id. When examining the definiteness of a term, courts “must take into 

account the inherent limitations of language,” and therefore “[s]ome modicum of uncertainty . . . is 

the price of ensuring the appropriate incentives for innovation.” Id. (internal quotation marks 

omitted). “At the same time, a patent must be precise enough to afford clear notice of what is 

claimed, thereby apprising the public of what is still open to them.” Id. at 2129 (internal quotation 

marks omitted). “Cognizant of the competing concerns,” the Supreme Court requires “that a 

patent’s claim, viewed in light of the specification and prosecution history, inform those skilled in 

the art about the scope of the invention with reasonable certainty.” Id.

The first step required is to define who is a person skilled in the relevant art. This patent 

was written for those who practice stem-cell transplantation or study stem-cell biology. A person 

skilled in the relevant art is therefore one who has obtained a Ph.D. in biological sciences or an 

M.D. In addition, this person is one with significant experience with stem-cell biology, 

hematopoiesis, and stem-cell transplantation.

Turning to the question of whether such a skilled artisan understands the phrase 

“hematopoietic stem cell mobilizing-effective amount of G-CSF,” Sandoz takes aim at the word 

“effective” and offers three arguments for why the term is indefinite. First, it argues neither the 

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claim language nor the specification inform skilled artisans about how many blood-producing 

stem cells must mobilize to be considered “effective.” In other words, a skilled artisan has no way 

to discern whether mobilization of one stem cell, ten stem cells, or a thousand stem cells is 

“effective.” Second, Sandoz insists the claim, specification, and prosecution history do not 

provide information for skilled artisans to tailor the procedure to the species of the patient (human, 

mouse, dog, horse, etc.). The final argument is that the patent does not explain how artisans 

should measure the level of stem-cell mobilization. At the time of the invention, practitioners 

knew of four methods for measuring the extent of stem cell mobilization, all of which varied 

considerably in terms of accuracy, consistency, and practicality. See Sandoz’s Expert Negrin 

Decl. ¶¶ 45-46. 

Whether adjectival limitations are indefinite depends on the context of each individual 

patent. In Takeda Pharm. Co. v. Mylan Inc., No. 13-CV-04001-LHK, 2014 WL 5862134, at 

*10-11 (N.D. Cal. Nov. 11, 2014), the district court deemed the term “effective amount” definite 

because the patent described the proper dose of the drug (“about 0.5 to 1,500 mg/day”), and the 

claim covered treatment of a specific type of disease—reflux esophagitis. Id. at *10. In contrast, 

another district court concluded the term “% identity” was indefinite because “the specification 

identifie[d] a non-inclusive list of five methods to calculate ‘% identity’ and provide[d] that 

sequence alignment can be performed using any commercially available or independently 

developed software.” Butamax Advanced Biofuels LLC v. Gevo, Inc., 117 F. Supp. 3d 632, 641 

(D. Del. 2015). Similarly, in Andrulis Pharm. Corp. v. Celgene Corp., No. CV 13-1644(RGA), 

2015 WL 3978578, at *3-4 (D. Del. June 26, 2015), the term “enhanced therapeutically-effective 

amounts of thalidomide” was held to be indefinite because “enhanced” could mean “less than 

additive, additive, or greater than additive.” Id. at *3.

Here, the claim itself offers little guidance, but the specification provides more direction. 

It teaches, “[t]he [G-CSF] dosage may depend on various factors such as mode of application, 

species, age, or individual condition. According to the invention, from 5 to 300 μg/kg/day of GCase 3:14-cv-04741-RS Document 205 Filed 08/04/16 Page 7 of 33
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CSF sc.2is applied.” Pai Decl. Ex. 1, ’427 Patent 3:4-7. G-CSF administration occurs “once per 

day over two to three days.” ’427 Patent 4:5-8. Amgen points to portions of the specification that 

explain, “[n]umerous substances” are capable of causing mobilization of blood-producing stem 

cells, such as G-CSF and “[s]ome chemotherapeutic agents.” ’427 Patent 1:32-37. These 

passages make clear that, at the time the patent was filed, skilled artisans knew G-CSF caused 

blood-producing stem cells to mobilize, and that any amount ranging from 5 to 300 μg/kg/day of 

G-CSF sc. would cause stem cells to mobilize enough to enable collection. 

The prosecution history of the ’427 patent offers skilled artisans further guidance and 

additional support for Amgen’s proposed construction. Three papers identified in the specification 

refer to various G-CSF dosage amounts within the range stated in the specification. Two papers 

examined the efficacy of subcutaneous doses of 10 μg/kg/day. Wu Decl. Ex 4 at 861 (Long et al., 

Cancer 76(5):860-68 (1995)); Wu Decl. Ex. 6 at 146 (Pierelli et al., J. Hematotherapy 2:145-53 

(1993)). Another study tested the comparative potency of subcutaneous or intravenous doses of 

10 μg/kg/day or 5 μg/kg/day. Wu Decl. Ex. 5 at 2177 (Nademanee et al., J. Clinical Oncology

12(10):2176-86 (1994)). These three studies supply a person skilled in the art with more 

information to determine with a reasonable degree of certainty how much G-CSF to administer to 

achieve more than a de minimus level of stem-cell mobilization.

While the range of the amounts of G-CSF to administer is admittedly wide and variable 

depending on the size or species of the subject, a skilled artisan is not without any guidance to 

figure out how much G-CSF to administer. After all, “breadth is not indefiniteness.” SmithKline 

Beecham Corp. v. Apotex Corp., 403 F.3d 1331, 1341 (Fed. Cir. 2005). To the extent a skilled 

artisan may have difficulty adjusting the amount of G-CSF to administer depending on the species 

of the subject, the lack of precision in the claim and specification impacts only his or her ability to 

practice all embodiments of the claim—a question of enablement, not indefiniteness. See Takeda, 

2014 WL 5862134, at *10 (citing Exxon Research & Eng’g Co. v. United States, 265 F.3d 1371, 

 

2

“sc.” stands for “subcutaneous.” Negrin Decl. ¶ 40.

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1382 (Fed. Cir. 2001) (noting that “‘inoperable embodiments’ raise ‘an issue of enablement, and 

not indefiniteness”)). Overall, the patent communicates the purpose of G-CSF administration: to 

cause more than a de minimus number of blood-producing stem cells to enter the peripheral blood. 

While the claim and specification could have offered more precise guideposts, the disclosures 

provide those skilled in the art with sufficient information to figure out how to accomplish that 

goal. Accordingly, the phrase “hematopoietic stem cell mobilizing-effective amount of G-CSF” is 

not indefinite. It will be construed as follows: “an amount of G-CSF effective to mobilize 

hematopoietic stem cells.”

2. “A method of treating a disease requiring peripheral stem cell transplantation in a 

patient in need of such treatment”

The second phrase to construe is the preamble to claim 1. Although it appears in only 

claim 1, claims 2, 3, 4, and 6 incorporate the preamble by reference. Both parties agree the 

preamble limits the scope of the claim, but they disagree about how to construe it. The crux of the 

dispute is about the phrase “a method of treating a disease requiring peripheral stem cell 

transplantation in a patient in need of such treatment.” Amgen construes the phrase as follows: 

“In the practice of the method, a patient in need of a stem cell transplant receives a transplant of 

peripheral stem cells.” Sandoz offers the following construction: “In the practice of the method 

of treating a disease, a patient receives a transplant of peripheral stem cells.” The fight boils down 

to whether peripheral stem cell transplantation is itself disease treatment, or whether it is a 

component of disease treatment to alleviate the side effects of treatment (namely chemotherapy). 

The text of the claim itself and the intrinsic record support Sandoz’s construction.

To begin, the phrase “such treatment” must have an antecedent. See Rapoport v. Dement, 

254 F.3d 1053, 1059 (Fed. Cir. 2001) (noting the phrase “to a patient in need of such treatment” 

must have an antecedent basis). Sandoz argues the antecedent is “a method of treating a disease,” 

whereas Amgen insists it refers back to “peripheral stem cell transplantation.” Under Sandoz’s 

construction, the treatment (usually chemotherapy) necessitates stem-cell transplantation. To 

practice the treatment method, the doctor mobilizes, collects, and transplants blood-producing 

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stem cells into the patient. In contrast, under Amgen’s reading it is the disease (primarily cancer) 

that requires peripheral stem cell transplantation. While “such treatment” surely requires an 

antecedent, both proposed constructions are grammatically correct, and therefore to construe the 

terms requires a more searching inquiry. 

The text of the whole claim lends support to Sandoz’s construction. The method claim 1 

includes two steps: (1) administration of G-CSF, and (2) administration of a chemotherapeutic 

agent. The claim describes the quantity of G-CSF to be administered as “stem cell mobilizing,” 

whereas the chemotherapeutic agent is described as “disease treating.” See ’427 Patent at 

10:26-29. In other words, one substance mobilizes stem cells, while the other treats a disease. 

The claim suggests the transplantation itself does not treat disease.

The specification bears out this interpretation. It explains the purpose of the claimed 

method: “The use of high-dosage chemotherapy or bone marrow ablation by irradiation requires 

subsequent incorporation of hematopoietic stem cells into the patient, in which case recovery of 

such cells is required.” ’427 Patent at 1:18-21. Mobilization of blood-forming stem cells “has a 

crucial influence on the efficiency of” peripheral stem cell recovery. ’427 Patent at 1:22-24. The 

method claimed by the patent improves upon the process of collecting stem cells by increasing the 

number of stem cells in the peripheral blood, thereby reducing the number of leukaphereses 

required. See ’427 Patent at 1:24-27 (“At present, 2-3 leukaphereses are required for successful 

peripheral stem cell transplantation, resulting in considerable stress for the patients.”); id. at 

1:55-61 (“As the required number of leukaphereses is extremely stressing for the patient in the 

run-up to the treatment of particular diseases, e.g., in preparing myeloablative or myelotoxic 

therapy, the invention was based on the object of achieving a superior yield of stem cells or a 

decrease in the number of leukophereses via enhanced mobilization of stem cells.”). Finally, the 

specification teaches that administration of G-CSF followed by administration of a 

chemotherapeutic agent is part of the “run-up to a, e.g. antitumor therapy,” and therefore is not the 

disease treatment itself. ’427 Patent at 4:24-25. 

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Thus, the specification clarifies any ambiguity in the text of the claim about whether 

peripheral stem-cell transplantation is a treatment for disease or a component of disease 

treatment.3 It is the latter. Accordingly, Sandoz has the better construction, and it is adopted.

3. “disease treating-effective amount of at least one chemotherapeutic agent”

The next phrase up for construction is “disease treating-effective amount of at least one 

chemotherapeutic agent.”

4

 It appears in claim 1, and the patentee also incorporated the term by 

reference into claims 2, 3, 4, and 6. Amgen proposes defining the phrase as “an amount of at least 

one chemotherapeutic agent sufficient to enhance the mobilization of stem cells for recovery from 

the blood for subsequent peripheral transplantation.” Sandoz offers the following construction: 

“an amount sufficient to treat a disease for which at least one chemotherapeutic agent is 

prescribed.” The crux of the dispute revolves around whether the chemotherapeutic agent treats a 

disease such as cancer (Sandoz’s construction), or whether the chemotherapeutic agent’s purpose 

is to mobilize blood-producing stem cells for collection and subsequent peripheral transplantation 

(Amgen’s construction). The text of the claim and the specification compel adoption of Sandoz’s 

proposal.

 

3

This is not to say all forms of peripheral stem-cell transplantation are not treatments. Sandoz’s 

expert witness, Robert S. Negrin, M.D., has explained the difference between two types of stemcell transplants: allogeneic transplants and autologous transplants. Allogeneic transplants involve 

transplantation of a healthy donor’s stem cells, and are used to treat certain cancers. See Negrin 

Sur-Reply Decl. ¶ 12. In contrast, autologous transplants involve using the patient’s own stem 

cells. Id. ¶ 11. Autologous transplants do not treat diseases; they counteract the negative side 

effects of disease treatments such as myelotoxic chemotherapy or radiation. Id. The ’427 Patent 

obviously addresses autologous transplants, not allogeneic transplants.

4

In Amgen, Inc. v. Apotex Inc., No. 15-61631-CIV, 2016 WL 1375566, at *5-6 (S.D. Fla. Apr. 7, 

2016), the district court construed this very phrase. The court adopted Amgen’s proposed 

construction, concluding a “disease treating-effective amount” of the chemotherapeutic agent is an 

amount “needed to achieve the goal of enhancing stem cell mobilization for recovery from blood 

and subsequent transplantation.” Id. at *6. Prior claim construction orders are not binding or 

dispositive unless “an earlier suit . . . trigger[s] application of the doctrine of collateral estoppel.” 

W. v. Quality Gold, Inc., No. 5:10-CV-03124-JF HRL, 2011 WL 6055424, at *2 (N.D. Cal. Sept. 

16, 2011). Sandoz was not a party to the Florida action, and therefore the doctrine of collateral 

estoppel is wholly inapplicable. 

In Apotex, rather than proposing a construction, the defendant argued the term “disease 

treating-effective amount” is indefinite. See Apotex, 2016 WL 1375566, at *5. The district court 

did not weigh in on the question presented here, and therefore its construction is of limited weight.

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“[T]he context in which a term is used in the asserted claim can be highly instructive.” 

Phillips, 415 F.3d at 1314. There are three parts to claim 1—the preamble and two limitations: 

the first limitation is a description of step one (administration of G-CSF); the second limitation is a 

description of step two (administration of the chemotherapeutic agent). Rather than referring to 

the two steps of the claimed process as “stem-cell mobilizing,” the patentee chose to use different 

descriptors for G-CSF and chemotherapeutic agents. G-CSF is “hematopoietic stem cell 

mobilizing,” whereas the chemotherapeutic agent is “disease treating.” See ’427 Patent at 

10:27-29. “Different claim terms are presumed to have different meanings.” Bd. of Regents v. 

BENQ Am. Corp., 533 F.3d 1362, 1371 (Fed. Cir. 2008). Here, the patentee chose to use two 

different words, and thus the two terms presumably carry different meanings. 

A natural reading of these two terms suggests they are not synonyms. Nevertheless, claims 

“do not stand alone. Rather they are part of a fully integrated written instrument, consisting 

principally of a specification that concludes with the claims.” Phillips, 811 F.3d at 1315 (internal 

quotation marks and citation omitted). Thus, if the specification suggests the two phrases describe 

similar functions, then the claim must be construed accordingly. Indeed, there is some evidence in 

the specification that the purpose of administering a chemotherapeutic agent is the same as that for

G-CSF administration. The specification teaches about stem-cell mobilizing characteristics of 

chemotherapeutic agents. See, e.g., ’427 1:35-36 (citing Richman et al., Blood, Vol. 47, No. 6 

1031 (1976)) (“Some chemotherapeutic agents are also known to possess the ability of mobilizing 

bone marrow stem cells . . . .”);’427 Patent at 1:5-9 (“The present invention relates to the novel 

use of G-CSF and a chemotherapeutic agent or a combination of chemotherapeutic agents to 

produce a pharmaceutical preparation for enhanced mobilization of hematopoietic stem cells in the 

treatment of diseases requiring peripheral stem cell transplantation.”); ’427 Patent at 3:13-17 

(“Surprisingly, it was determined that administration of G-CSF prior to opening of the endothelial 

barrier induced by chemotherapeutic agents significantly increases the stem cell mobilization and 

thus, can improve leukapheresis efficiency.”). Yet, these references to the chemotherapeutic 

agent’s ability to open the endothelial barrier cannot supplant language of the claim itself. In 

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claim 4, the patentee chose to describe one function of a chemotherapeutic agent: its ability to 

“open[] the endothelial barrier of the patient to render the endothelial barrier permeable for stem 

cells.” ’427 Patent at 10:36-38. Claim 4 demonstrates the patentee’s ability to differentiate 

between two of chemotherapeutic agents’ known functions: opening the endothelial barrier and 

treating disease (typically cancer). Thus, while the specification provides critical context for 

understanding the claim language, it cannot “be used to rewrite, the chosen claim language. 

Specifications teach. Claims claim.” SuperGuide Corp. v. DirecTV Enterprises, Inc., 358 F.3d 

870, 875 (Fed. Cir. 2004) (internal quotation marks omitted). 

Here, in claim 1, the patentee claimed the disease-treating function of chemotherapeutic 

agents. It shall therefore be construed as follows: “an amount sufficient to treat a disease for 

which at least one chemotherapeutic agent is prescribed.”

4. “chemotherapeutic agent”

The term “chemotherapeutic agent” appears in claims 1, 4, 5, and 6, and claims 2 and 3 

incorporate the term by reference to claim 1. On the one hand, Amgen would construe the term as 

an “exogenous substance that is capable of damaging or destroying microorganisms, parasites or 

tumor cells and that may open the endothelial barrier.” On the other hand, Sandoz would prefer to 

construe the phrase as an “exogenous substance suited and used to damage or destroy 

microorganisms, parasites or tumor cells.” While the two constructions are similar, there are two 

points of dispute. First, they disagree about whether chemotherapeutic agents perform two 

functions (damaging and destroying microorganisms and opening the endothelial barrier), or just 

one (damaging and destroying microorganisms). Second, they part company over whether the 

chemotherapeutic agent must be “capable of” those functions, or “suited and used” for a certain 

purpose. At the Markman hearing, Amgen agreed to drop any reference to opening the endothelial 

barrier from its construction. Dkt. No. 199, Hr’g Tr. 118:23-119:1. Thus, the only remaining 

dispute is whether to use the words “capable of” or “suited and used for.”

Sandoz generated its construction directly from the specification, which defines 

“chemotherapeutic agents.” ’427 Patent 2:37-39 (“[C]hemotherapeutic agents are understood to 

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be exogenous substances suited and used to damage or destroy microorganisms, parasites or tumor 

cells.”). “[T]he specification may reveal a special definition given to a claim term by the patentee 

that differs from the meaning it would otherwise possess.” Phillips, 415 F.3d at 1316. It may also 

“reveal an intentional disclaimer, or disavowal, of claim scope by the inventor.” Id. When the 

inventor provides a definition, his or her chosen lexicography is dispositive. Id. Amgen must 

therefore mount a strong case in order to change the definition the patentee included in the 

specification.

Amgen tries to do so by arguing the definition from the specification might be read to limit 

the scope of the claim to those chemotherapeutic agents known and used at the time of the 

invention. As a general matter, patentees need not “describe in [their] specification every 

conceivable and possible future embodiment of [their] invention.” SRI Int’l, 775 F.2d at 1121. 

The specification lists various types of cytostatic agents (alkylating agents, metal complex 

cytostatic agents, antimetabolites, natural substances, antibiotic agents, hormones and hormone 

antagonists, and “other compounds”) and offers examples of each group. See ’427 Patent at 

2:40-54. This list of examples suggests the patentee did not intend the claim to be limited to those 

chemotherapeutic agents known and used at the time of the invention. 

This fact alone does not necessarily militate in favor of deviating from the definition 

provided in the specification or Amgen’s proposed construction. The concern is that there are 

many agents, like battery acid, which are technically capable of damaging or destroying 

microorganisms, parasites, and tumors, but are not used or suited for that purpose.5 

 

5

In Apotex, the district court adopted the construction of “chemotherapeutic agent” Amgen now 

offers. See 2016 WL 1375566, at *5. Once again, the Apotex court’s constructions are of limited 

persuasive value because it confronted different proposed constructions than those at issue here. 

Apotex suggested the following construction, which limited chemotherapeutic agents to those that 

open the endothelial barrier: “Therapeutic agents which open the endothelial barrier, rendering it 

permeable for stem cells and/or exogenous substances suited and used to damage or destroy 

microorganisms, parasites or tumors.” Id. Thus, the district court did not address or consider 

whether “capable” is a synonym for “suited and used for,” or whether the construction of this term 

should mention anything about opening the endothelial barrier.

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At the hearing, Amgen offered two alternative constructions: “an exogenous substance 

that is suitable for use to damage or destroy microorganisms, parasites or tumor cells and that may 

open the endothelial barrier” or “an exogenous substance that is suited to damage or destroy . . . .” 

See Tr. Hr’g 121:1-4; 122:14-22. Sandoz did not agree to either proposal for the simple reason 

that the patentee chose a definition and cannot change that definition at a later time, and its 

position is certainly correct as a matter of law. Phillips, 415 F.3d at 1316. 

That there may be factual disputes as this case progresses does not counsel in favor of 

adopting Amgen’s construction. In the absence of any reason to deviate from the patentee’s 

definition of “chemotherapeutic agent,” it shall be adopted for the purposes of this litigation. 

Accordingly, the term “chemotherapeutic agent” shall mean “exogenous substance suited and used 

to damage or destroy microorganisms, parasites, or tumor cells.”

5. “comprising administering . . . G-CSF; and thereafter administering . . . at least one 

chemotherapeutic agent”

The fifth phrase requiring construction appears or is incorporated into claims 1, 2, 3, 4, and 

6: “comprising administering . . . G-CSF; and thereafter administering . . . at least one 

chemotherapeutic agent.” Amgen proposes the following construction: “G-CSF and the at least 

one chemotherapeutic agent are given in combination for purposes of stem cell mobilization, and 

the order in which G-CSF and the chemotherapeutic agent(s) are administered for that purpose is 

G-CSF first followed by the chemotherapeutic agent(s).”6 Sandoz contends the word 

“comprising” means “including but not limited to,” and allows for additional steps before, in 

 

6

Initially, Amgen proposed a lengthier construction of the phrase: “G-CSF and the at least one 

chemotherapeutic agent are given in combination for purposes of stem cell mobilization, and the 

order in which G-CSF and the chemotherapeutic agent(s) are administered for that purpose is GCSF first followed by the chemotherapeutic agent(s). Other than the foregoing stem cell 

mobilization step, the method for treating a disease requiring peripheral stem cell transplantation 

involves additional steps such as collection of cells by leukapheresis, myeloablative and/or 

myelotoxic therapy, and transplanting the collected peripheral stem cells back into the patient. 

The term ‘comprising’ allows for these additional steps.” At the Markman hearing, Amgen 

withdrew the second sentence, and so this order will focus on only the first. See Tr. Hr’g 

137:3-138:6 (“[W]e would be perfectly happy to just go with the first sentence of the proposal.”).

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between, and after the steps recited in the claim. It also offers the following construction of the 

remainder of the phrase: “In the practice of the method, at least one administration of G-CSF must 

occur before at least one administration of a chemotherapeutic agent.” Thus, there are two 

disputes to resolve: (1) whether to construe the word “comprising” (and how), and (2) whether to 

include some explanation about the purpose of each step. For the reasons discussed below, the 

construction Sandoz advances must be adopted. 

“Comprising” is a term of art, which means “including but not limited to.” Exergen Corp. 

v. Wal-Mart Stores, Inc., 575 F.3d 1312, 1319 (Fed. Cir. 2009). Sandoz’s thus accords with 

longstanding rules of patent interpretation. Amgen urges declining to adopt the traditional 

construction of the word “comprising” out of fear that such construction would obfuscate the 

novelty of the invention, i.e. the precise order of administration (G-CSF first, and 

chemotherapeutic agent(s) second).7 The trouble with this position is the simple fact the word 

“comprising” appears in the claim, and therefore must be construed. Amgen has not adequately 

explained how Sandoz’s construction fails to convey the essence of the method claimed: the order 

of administration. Accordingly, the word “comprising” must be construed as usual to mean 

“including but not limited to.” This construction naturally implies there may be steps before, in 

between, and after the steps recited in the claim.

The crux of the second dispute is whether Amgen’s proposed construction improperly 

imports a purpose limitation into the claim. Critically, Amgen’s suggested reading emphasizes 

that the purpose of administering a chemotherapeutic agent is to mobilize blood-forming stem 

 

7

Indeed, numerous portions of the specification make clear the invention relates to the timing of 

the administration of G-CSF and the chemotherapeutic agent—G-CSF first, the chemotherapeutic 

agent second. See ’427 Patent at 3:18-23 (“By administering G-CSF prior to administration of the 

chemotherapeutic agent(s) . . .”); id. at 1:66-21:11 (“The G-CSF and chemotherapeutic agent 

administration forms can be taken out separately and administered successively according to the 

optimum application regimen.”); id. at 3:5-17 (“The administration of the chemotherapeutic 

agent(s) is initiated either immediately after the second or third G-CSF injection or on the fourth 

day . . . . [I]t was determined that administration of G-CSF prior to opening of the endothelial 

barrier induced by chemotherapeutic agents significantly increases the stem cell mobilization . . . 

.”); id. at 3:31-41 (“[T]he administration of G-CSF prior to administration of the chemotherapeutic 

agent . . . for enhanced mobilization of hematopoietic stem cells.”). 

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cells, and not to treat disease. As addressed above, Sandoz hotly contests this point. No 

reiteration of the arguments about whether the purpose of administration of the chemotherapeutic 

agent is necessary for there is no textual basis to import a purpose limitation into the claim. The 

text of the claim and the specification make clear the method encompasses a specific order of 

administration (G-CSF, followed by a chemotherapeutic agent). Sandoz’s proposed construction 

aligns with both, and therefore must be adopted in full. Accordingly, the word “comprising” 

means “including but not limited to,” and allows for additional steps before, in between, and after 

the steps recited in the claim. In the practice of the method, at least one administration of G-CSF 

must occur before at least one administration of a chemotherapeutic agent.

6. “opens the endothelial barrier of the patient to render the endothelial barrier 

permeable for stem cells”

The final term in the ’427 Patent to construe pertains to only claim 4: “opens the 

endothelial barrier of the patient to render the endothelial barrier permeable for stem cells.” 

Amgen proposes construing the claim to mean “enhances the transit of stem cells from the bone 

marrow to the peripheral blood,” whereas Sandoz contends it should mean “disrupts the bone 

marrow endothelial barrier.” This dispute boils down to whether the phrase encompasses all 

mechanisms by which the chemotherapeutic agent allows stem cells to travel from bone marrow 

into the peripheral blood or whether the claim is limited to one mechanism, namely breaking down 

the barrier altogether. 

The text of the claim does not resolve this dispute, but the specification offers some 

guidance. At the time of the alleged invention, skilled artisans were aware that administration of 

cytotoxic agents caused the number of stem cells to increase in the peripheral blood. What was 

unknown at the time was how exactly blood cells moved from bone marrow into the peripheral 

blood. One article described the process as an “[i]njury to the supporting structure of the 

marrow.” Wu Decl. Ex. 10 at 1037, Richman et al., Blood 47(6): 1031-39 (1976) (cited at ’427 

Patent at 1:35-37). Another researcher explained, “[A] cytotoxic conditioning regimen can induce 

membrane instability leading to massive loss of the endothelial membrane.” Wu Decl. Ex. 11 at 

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373, Shirota et al., Exp. Hematol 19:369-73 (1991) (cited by ’427 Patent at 1:50-54). Yet another 

researcher described the process as a “disrupt[ion] [of] normal marrow endothelial cell barriers.” 

Wu Decl. Ex. 12 at 1965 (Nebren et al., Blood 81(7):1960-67 (1993) (cited by ’427 Patent cover). 

Researchers had observed disruption of the endothelial barrier of some kind, which then caused 

the stem cells to enter the peripheral blood stream. While researchers generally abstained from 

identifying this disruption as the only reason blood-producing stem cells are released into the 

blood stream, the available articles would inform a skilled artisan that the probable method 

involved destruction of the endothelial barrier. Amgen believes its construction captures this state 

of affairs. 

Sandoz for its part has derived its construction from the prosecution history. During the 

patent prosecution, the PTO rejected the claim because the specification did not adequately 

disclose information about how to use chemotherapeutic agents that increase the permeability of 

the endothelial barrier. Pai Decl. Ex. 7, June 30, 2000 Resp. to Office Action at 3. In response to 

this inquiry, the patentee stated, “cyclophosphamide is one of the examples of cytotoxic agents 

that disrupt normal bone marrow endothelial cell barriers.” Id. Sandoz argues that this history 

suggests the clarification about the meaning of the word “open” and using the term “disrupt” as its 

synonym was an essential precursor for approval. 

Ultimately, Sandoz’s position boils down to two concerns. The first issue involves

whether jurors might believe “opening” the endothelial barrier leaves the barrier intact, which 

implies a temporary removal, like a door or a curtain. “Disrupt” on the other hand connotes a 

more damaging process, whereby the barrier may repair over time, but not immediately. Amgen 

maintains there may be mechanisms for opening the endothelial barrier that do not involve 

disruption. The trouble with Amgen’s proposed construction is the fact it untethers the claim from 

the specification and the prosecution history. That the patentee chose to use “disrupt” as a 

synonym for “open” with the PTO militates in favor of using “disrupt” in the construction of this 

phrase. 

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Second, Sandoz contends the articles referenced in the specification merely hypothesize 

about how opening the endothelial barrier facilitates stem-cell transit from bone marrow into the 

peripheral drug. An open door certainly facilitates movement from the outside to the inside, but it

does not cause such movement. During the Markman hearing, Sandoz agreed to amend its 

proposed construction to include a purpose limitation: to disrupt the bone marrow endothelial 

barrier to facilitate the permeability of the endothelial barrier for stem cells. Tr. Hr’g 156:9–

157:4. The words “facilitate the permeability of the endothelial barrier for stem cells” appears in 

the specification, ’427 Patent at 1:53–55, and therefore resolves at least one of Amgen’s concerns, 

namely that the construction must communicate the purpose of the opening, see Tr. Hr’g 158:9 –

159:12 (Amgen counsel: “I don’t think we have any difficulty with the language that’s in the 

specification. . . . If we building the idea that its’ facilitating permeability, maybe we have 

captured that.”). 

All in all, the following construction aligns with the specification and prosecution history, 

and is therefore adopted: “disrupts the bone marrow endothelial barrier to facilitate permeability 

of the endothelial barrier for stem cells.” 

B. The ’878 Patent

Recombinant proteins are genetically engineered proteins. Scientists introduce human 

DNA encoding into a host cell of a different species, such as E. Coli, to create recombinant 

proteins. Introduction of human DNA into the host cell causes the bacteria to produce human 

proteins even though the bacteria would not produce such proteins naturally. This process has 

been used to engineer various human proteins since the 1980s. 

To be therapeutically useful, a recombinant protein must attain a three-dimensional shape. 

Trouble arises when the host cells produce the recombinant proteins “unfolded,” meaning the 

proteins do not have the proper three-dimensional shape. These unfolded recombinant proteins 

accumulate in the host cell and form insoluble aggregates called “inclusion bodies.” To remedy 

this problem, scientists break open (lyse) the host cell to release the inclusion bodies. Next, the 

scientists solubilize the inclusion bodies, which is a process of mixing the protein with various 

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chemicals to create a solution. That solution is then combined with a “refold buffer” to cause the 

protein to take a workable, three-dimensional shape. 

Once the protein has refolded, the scientists must then separate the refolded recombinant 

protein from the chemicals used to solubilize and to refold the protein. This step is called 

purification and typically involves a “separation matrix.” The separation matrix utilizes 

characteristics of the protein to be isolated to trap the protein in the matrix. The unwanted 

chemicals and proteins that do not have the targeted properties will not associate with the 

separation matrix and can be discarded. 

There are two types of purification: flow-through purification and capture purification. 

The process of flow-through purification involves applying the solution containing the refolded 

protein to a resin. Resin attracts the chemicals used to solubilize and to refold the protein. The 

refolded proteins do not attach to the resin, and therefore they “flow through” the resin and remain 

in the solution. 

In contrast, capture purification utilizes a resin designed to trap protein. The unwanted 

substances and chemicals stay in the solution and flow over the resin. Scientists discard the 

solution containing the unwanted contaminants and chemicals, leaving only the resin with the 

protein to be purified. The process of elation causes the resin to release the purified protein.

At the time of the alleged invention, skilled artisans believed the solution containing the 

solubilized and refolded protein had to be diluted to remove certain components of the refold 

solution before they could apply the separation matrix to it. Pai Decl. Ex. 2, Patent ’878 at 

1:44-46. Skilled artisans believed these contaminants would interfere with the protein’s ability to 

affiliate with the separation matrix. The patentees allegedly discovered that this dilution step was 

unnecessary; scientists can apply the separation matrix to the refolding solution without diluting 

the solution first. ’878 Patent at 15:33-37. The method disclosed in the patent removes a costly, 

time-consuming step in the purification process. ’878 Patent at 4:55-60.

1. “directly applying the refold solution to a separation matrix”

The first phrase of the ’878 Patent to construe appears in claims 7, 8, 11, 13, 14, 15, 16, 

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and 17. Amgen construes the phrase “directly applying the refold solution to a separation matrix” 

to mean “applying the refold solution to a column that contains the separation matrix without 

removing components of or diluting the refold solution.” Sandoz offers a slightly different 

construction of the phrase: “applying the refold solution to a separation matrix without diluting 

the refold solution or removing one or more of a denaturant, a reductant, a surfactant, an 

aggregation suppressor, a protein stabilizer, and a redox component.” There are two points of 

disagreement between the parties. First, Amgen does not wish to list the components of the refold 

solution, whereas Sandoz believes such components should be specified. The crux of the dispute 

is whether the claim allows for steps between the refolding process and the purification process, 

which remove components of the refold solution that are not required for refolding. Second, they 

part company over whether the refold solution is applied to a column or whether the claim covers 

other methods of applying separation matrices, such as batch processes. For the reasons discussed 

below the phrase will be construed as follows: “applying the refold solution to a separation matrix 

without removing components of or diluting the refold solution.”

a. “Directly Applying”8

Amgen and Sandoz agree the patent teaches a method of purification that does not require 

dilution of the refold solution. Sandoz’s construction is drawn from the claim itself, which lists the 

components “comprising” a solubilization solution: one or more of a denaturant, a reductant, and 

a surfactant. ’878 Patent at 22:9-13. Claim 7 further defines a “refold solution” as “comprising 

the solubilization solution and a refold buffer.” ’878 Patent at 22:14-15. The “refold buffer” 

“compris[es] one or more of” a denaturant, an aggregation suppressor, a protein stabilizer, and a 

redox component. ’878 Patent at 22:15-20. Thus, according to Sandoz’s expert, Nigel J. 

 

8 Along with the reply brief, Amgen submitted a declaration to rebut the extrinsic evidence Sandoz 

submitted. Sandoz sought to strike the declaration or, in the alternative, to file a sur-reply brief. 

Because the submission of new evidence and new argument in reply was improper, Sandoz 

received leave to file a sur-reply. One of the sur-reply declarations submitted included an 

interrogatory response. Amgen objected to the admission of this exhibit, but really used the 

objection as an opportunity to argue why the submitted exhibit did not actually support Sandoz’s 

argument. Accordingly, the objection is overruled.

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Titchener-Hooker, Ph.D., a skilled artisan would understand the “refold solution,” which is

applied to the separation matrix includes the listed components. Sandoz’s Expert TitchenerHooker Decl. ¶¶ 31-32. 

Amgen contends the word “directly” means there are no intermediary steps of any kind 

between refolding and purification. The dispute about proper construction of the word “directly 

revolves around whether the claim allows for removal of components of the refold solution that 

are not required for refolding. 

The proper starting point is, of course, the text of the claim. A person skilled in the art

could read the claim and reasonably conclude no dilution steps of any kind are allowed between 

refolding and washing. Yet, “directly” could also mean the refold solution need not pass through 

something to come into contact with the separation matrix. Accordingly, the text of the claim 

itself does not resolve the dispute.

The specification teaches the method claimed involves applying “the refold solution 

comprising the refolded protein of interest” “directly to the separation matrix, without the need for 

diluting or removing the components of the solution required for refolding the protein.” ’878 

Patent at 15:25-29 (emphasis added). Similarly, in the prosecution history, the patentee used 

related language after the PTO rejected the proposed claims because it believed U.S. Patent No. 

7,138,370 anticipated the claimed method. Patent ’370 disclosed a method of protein purification 

requiring three processing steps before the refold solution could be applied to the separation 

matrix: dialysis, precipitation, and centrifugation. To remedy this problem, the patentee added the 

word “directly” to the claim to emphasize that the disclosed method did not require removal of 

“the components of the solution required for refolding the protein.” Wu Decl. Ex. 13 at 3. Amgen 

insists these statements in the specification and prosecution history make clear no dilution 

whatsoever is required. 

The trouble with this position is the fact claim 7’s steps (c) and (d) and preamble recites 

the components that comprise the refold solution: one or more of a denaturant, a reductant, a 

surfactant, an aggregation suppressor, a protein stabilizer, and a redox component—the very 

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components listed in Sandoz’s construction. That said, Sandoz’s construction does not fully 

capture the claim because, in the world of patents, the word “comprising” means “including but 

not limited to.” Exergen, 575 F.3d at 1319. The six components listed in the claim are not 

necessarily the only components of the refold solution. Moreover, the patentee’s attempt to 

distinguish the claimed method from the prior art, and the ’370 Patent, in particular, clarify that 

the patentee believed there should not be any intermediary steps between the refolding process and 

application of such solution to the separation matrix. 

b. “Column”

The second point of conflict is whether the refold solution must be applied to a column 

containing the separation matrix or whether the claim contemplates other methods of bringing the 

separation matrix in contact with the refold solution. Amgen and Sandoz agree on at least one 

point: that the claim, specification, and prosecution history all contemplate that scientists could 

load the refold solution into a column containing the separation matrix. Conflict has arisen, 

however, because there are various methods of chromatography used to bring into contact 

separation matrices and refold solution. The column method involves loading the refold solution 

into a column containing a separation matrix. As the solution flows down the column, it flows 

past the separation matrix and down into a collection vessel, where either the contaminants or 

protein collect. There are, however, other methods scientists used to accomplish the same goal, 

such as batch processing and filtration systems. ’878 Patent at 16:47-54. The batch method 

employs resin beads with the separation matrices. Scientists pour the refold solution into a 

container containing these resin beads, and then they discard the excess solution. Despite the fact 

that there are multiple methods of chromatography, Amgen contends claim 7 is limited to the 

column method even though the claim does not specify the chromatography method used. 

The most significant problem with Amgen’s proposal is that the word “column” does not 

appear in the claim, and thus there is no reasonable argument for the proposition “column” is a 

synonym for any word appearing therein. “[A] bedrock principle of patent law [is] that the claims 

of a patent define the invention to which the patentee is entitled the right to exclude.” Phillips, 

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415 F.3d at 1312 (internal quotation marks omitted). Amgen therefore faces an uphill battle to 

show its construction including the word “column” is proper.

Amgen first turns to the specification, which describes three embodiments of the method—

all of which describe column chromatography. Sandoz correctly notes the first two examples 

describe affinity separation matrices, which do not pertain to claim 7. Nevertheless, a skilled 

artisan reading the specification would read about only column processes—a fact suggesting, but 

not establishing, that the method involves column application. Yet, the specification also teaches: 

[A]ny or all steps of the invention can be carried out by any 

mechanical means. As noted, the separation matrix can be disposed 

in a column. The column can be run with or without pressure and 

from top to bottom or bottom to top. The direction of the flow of 

fluid in the column can be reversed during the purification process. 

Purifications can also be carried out using a batch process in which 

the solid support is separated from the liquid used to load, wash, and 

elute the sample by any suitable means, including gravity, 

centrifugation, or filtration. Moreover, purifications can also be 

carried out by contacting the sample with a filter that adsorbs or 

retains some molecules in the sample more strongly than others.

’878 Patent at 16:42-54 (emphasis added). The specification thus makes clear the method is not 

limited to column chromatography alone and even offers additional methods. In light of the fact 

the Federal Circuit has rejected the notion “that if a patent describes a single embodiment, the 

claims of the patent must be construed as being limited to that embodiment,” Liebel-Flarsheim 

Co. v. Medrad, Inc., 358 F.3d 898, 906 (Fed. Cir. 2004), the simple fact most examples disclosed 

in the specification involve column chromatography is not dispositive. 

The second problem with Amgen’s “column” proposal is that the specification describes 

the process of putting the refold mixture into the column as “loading,” whereas the word 

“applying” implies a broader range of mechanisms. See Titchener-Hooker Decl. ¶35. For that 

reason, Titchener-Hooker contends that had the patentee wished to limit the method claimed to the 

column process, it should have used the word “loading.” Id. (citing ’878 Patent at 18:7-17, 

19:4-17). 

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In sum, the text of the claim and intrinsic record do not support Amgen’s proposal to limit 

the claim to the column process. At the same time, neither the intrinsic record nor the extrinsic 

record support Sandoz’s attempt to list the components of the refold solution that need not be 

removed before the solution is applied to the separation matrix. Accordingly the phrase “directly 

applying the refold solution to a separation matrix must be construed as follows: “applying the 

refold solution to a separation matrix without removing components of or diluting the refold 

solution.”

2. “under conditions suitable for the protein to associate with the matrix”

The phrase “under conditions suitable for the protein to associate with the matrix” relates 

to claims 7, 8, 11, 13, 14, 15, 16, and 17. There are two points of disagreement about how 

properly to construe this phrase: the construction of the words “protein” and “associate.” For the 

reasons discussed below, the phrase shall be construed as follows: “under conditions suitable for 

the protein to be purified to bind to the matrix.”

a. Protein

Amgen believes the word “protein” refers to any protein expressed by the non-mammalian 

expression system, not just the protein of interest, i.e., the recombinant protein expressed by the 

host cell. In contrast, Sandoz argues “protein” refers to a specific protein the scientists intended 

the non-mammalian organism to express (G-CSF, for example).

Both parties argue the text of the claim supports their respective constructions. Amgen 

points to the preamble of claim 7: “A method of purifying a protein expressed in a non-native 

limited solubility form in a non-mammalian expression system . . . .” ’878 Patent at 22:3-5. The 

patentee chose to use “a protein” instead of “the protein” to make clear the method could be used 

to capture any protein expressed by a non-mammalian organism. 

More importantly, the patentee defined the word “protein” in the specification as follows: 

“the terms ‘protein’ and ‘polypeptide’ are used interchangeably and mean any chain of at least five 

naturally or non-naturally occurring amino acids linked by peptide bonds.” ’878 Patent at 

5:62-65. When an inventor has expressly defined a term in the specification, it controls for 

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construction purposes. See Phillips, 415 F.3d at 1316. In contrast, the patentee refers to the 

“protein of interest,” meaning the protein the scientists caused bacteria to express, throughout the 

disclosure. See e.g., ’878 Patent at 4:8-9 (“[T]he present invention relates to a method of isolating 

a protein of interest . . . .”); ’878 Patent at 4:31-32 (same). According to Amgen, the patentee’s 

conscious decision to use the word “protein” instead of “protein of interest” in claim 7’s text is 

significant and counsels in favor of using the specification’s definition of “protein.”

Sandoz begins with the text and structure of the claim. Step (a) of Claim 7 involves 

“expressing a protein,” whereas steps (c), (e), and (g) involve doing something to “the protein.” 

’878 Patent at 22:3-6, 22:9-25. The Federal Circuit has explained “[s]ubsequent use of the definite 

articles ‘the’ or ‘said’ in a claim refers back to the same term recited earlier in the claim.” Wi-Lan, 

Inc. v. Apple, Inc., 811 F.3d 455, 462 (Fed. Cir. 2016). Thus, Sandoz contends the steps refer back 

to the antecedent basis: the protein expressed in a non-native expression system is the protein to 

be purified. 

In addition, Sandoz correctly points out that the method claimed is one of protein 

purification, and therefore all steps listed in the claim drive towards the purification of one specific 

protein. Indeed, the specification teaches, “[a]fter the protein of interest has associated with the 

separation matrix the separation matrix is washed to remove unbound protein, lysate, impurities 

and unwanted components of the refold solution.” ’878 Patent at 15:43-46. The process of 

washing removes unwanted protein from the refold mixture, leaving only the sought-after protein 

stuck to the separation matrix. Once all unwanted materials have been washed away, the final step 

of the claimed process is elution, whereby the protein disassociates from the matrix. The end 

result is a clean protein ready for future use. All these steps lead to the electable conclusion the 

method claimed and the steps claim 7 describes target a specific protein.

That the clean protein emerging from the process is the expressed protein does not, 

however, necessarily follow from the text of the claim. Accordingly, Sandoz’s construction must 

be rejected for that reason. Nevertheless, the method claimed is also more targeted than Amgen 

suggested. The targeted protein is the protein to be purified. Thus, in the context of claim 7 (and 

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all derivative claims), the word “protein” means “the protein to be purified.”9

b. Associate

The parties also dispute whether “associate” is a synonym for “bind.” Amgen insists 

binding is merely one of the mechanisms by which proteins associate with separation matrices. 

Sandoz believes binding is the only mechanism by which the proteins interact with the separation 

matrix.

Amgen derives its construction from the specification and its definition of “separation 

matrix”:

As used herein, the term “separation matrix” means any absorbent 

material that utilizes specific, reversible interactions between 

synthetic and/or biomolecules, e.g., the property of Protein A to bind 

to an Fc region of an IgG antibody or other Fc-containing protein, in 

order to effect the separation of the protein from its environment. In 

other embodiments the specific, reversible interactions can be 

base[d] on a property such as isoelectric point, hydrophobicity, or 

size.

’878 Patent at 14:65-15:5 (emphasis added). Amgen reads this section to mean binding is just an 

example of the type of reversible interactions the process involves, whereas other embodiments of 

the method involve resins that retard the flow of the refold solution through the column or which 

trap large proteins and permit smaller proteins to flow through. While there is a temptation to treat 

the specification’s definition of “separation matrix” as a definition for associate, it is not. The 

specification defines “separation matrix,” and not “associate.” Accordingly, the specification 

offers some, but not definitive, support for Amgen’s proposed construction.

Sandoz has identified portions of the specification that support its position, where the 

patentee used the words “associate” and “bind” interchangeably. For example: “After the protein 

of interest has associated with the separation matrix, the separation matrix is washed to remove 

unbound protein, lysate, impurities and unwanted components of the refold solution.” ’878 Patent 

 

9 Recently, the Apotex court construed the word “protein” in accord with Amgen’s proposed 

construction. See Dkt. 195-1 at 14-17. While the court’s opinion is persuasive authority, its value 

goes only so far. First, the court was construing a different patent. Second, in Apotex, the 

defendant argued the word “protein” should be construed to mean “protein of interest,” whereas 

Sandoz has not proposed such a construction.

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at 15:43-46 (emphasis added). The patentee differentiated between proteins “associated with” the 

separation matrices and those components and proteins “unbound” from the matrices—a telling 

choice of words which implies the words are synonyms for the same process. In addition, when 

describing the elution process, the specification teaches, “[t]he protein of interest can be eluted 

using a solution that interferes with the binding of the absorbent component of the separation 

matrix to the protein.” ’878 Patent at 15:65-67. Thus, the specification equates binding with 

associating. 

Sandoz’s final argument is that the other steps listed in the claim clarify that “associate” 

means “bind.” Step (g) of claim 7 states, “the separation matrix is a non-affinity resin selected 

from the group consisting of ion exchange, mixed mode, and a hydrophobic interaction resin.” 

’878 Patent at 22:25-28. Figure 4 of the patent, titled “demonstration of Dynamic Binding 

Capacity for Ion Exchangers and Mixed mode Resins,” describes “a plot demonstrating the 

binding profiles of a refolded, non-mammalian non-native limited solubility complex protein to

six different ion exchange resins.” ’878 Patent at 3:22-29, Figure 4. This figure, Sandoz argues, 

demonstrates the ion exchanges and mixed mode resins operate by binding to proteins of interest. 

Ultimately, Amgen’s proposed construction does not make sense in the context of the 

claim as a whole. There are some interactions between resin and protein, which do not facilitate 

protein capture. For example, the proteins and resins may repel one another, but the repellence 

does not facilitate protein capture or purification. Although Amgen has provided examples of how 

proteins interact with separation matrices that do not involve a binding mechanism, they do not 

lend support for its construction. Sizing resins that trap proteins of a certain size while allowing 

smaller components to pass through are not non-affinity resins. Claim 7 discloses a capture 

method involving a non-affinity resin, see ’878 Patent at 22:26, and therefore sheds no light on the 

question of whether the claimed method covers interactions other than binding interactions. 

Similarly, isocratic protein separations, which retard the transit of some proteins moving through a 

column containing a separation matrix, do not employ “reversible interactions.” The interaction 

between the resin and the protein never reverses; the protein simply takes longer to pass through 

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the column. See Titchener-Hooker Sur-Reply Decl. ¶ 40.

Ultimately, most problematic aspect of Amgen’s proposed construction is that it is 

confusing and no clearer than the text of the claim itself. Accordingly, the word “associate” will 

be construed to mean “bind.” 

c. “washing the separation matrix”

The phrase “washing the separation matrix” must be construed to shed light on the 

meaning of claims 7, 8, 11, 13, 14, 15, 16, and 17. Amgen proposes construing the phrase as 

“adding a solution into the column that contains the separation matrix, to remove materials in the 

refold solution that do not interact with the separation matrix.” Sandoz on the other hand proposes 

the following construction: “applying a solution to remove unbound protein, lysate, impurities, 

and unwanted components of the refold solution from the separation matrix while preserving 

binding of the expressed protein.”

The parties’ disagreements are familiar and involve the meaning of “associate,” whether 

the chromatography method described is the column method, and whether the protein captured is 

the expressed protein. Each of these issues has been previously addressed and resolved. The 

claim shall not be limited to the column method of chromatography. The claim covers the capture 

of proteins other than the protein of interest. Finally, the proteins bind to the separation matrix 

when they “associate” with it. 

Nevertheless, there remains one material difference between the two proposed 

constructions about which the parties offer no argument for their disagreement: whether to list the 

components to be washed away. Sandoz lists those components (lysate, unbound protein, 

impurities, etc.), whereas Amgen suggests anything that “do[es] not interact with the separation 

matrix” will be removed. Sandoz offers no reason to list (or to limit) the components to be 

washed away. Amgen’s proposal is therefore not only simpler, but seems accurately to describe 

the process set forth in claim 7. 

In sum, the phrase must be construed as a hybrid of the two proposals. “Washing the 

separation matrix” shall mean “adding a solution to the separation matrix to remove materials in 

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the refold solution while preserving binding of the protein to be purified.”

d. “eluting the protein from the separation matrix”

The final phrase to construe—“eluting the protein from the separation matrix”— informs 

the scope of claims 7, 8, 11, 13, 14, 15, 16, and 17. Amgen would construe the phrase to mean 

“adding a solution into the column that contains the separation matrix, which as the effect of 

reversing the interactions between protein and the separation matrix.” Sandoz proposes to 

construe the phrase to mean “applying a solution that reverses the binding of the expressed protein 

to the separation matrix.” Under Sandoz’s proposed construction, “this step must occur after the 

step of ‘washing the separation matrix.’”

The disputes about how properly to construe the phrase are linked to the parties’ 

disagreement about the meaning of “associate,” “protein,” and “separation matrix,” and have been 

resolved. There is, however, one unique feature of this phrase: whether the eluting step must 

occur after the washing step. Amgen believes this claim does not properly present the issue of the 

order of the steps because Sandoz did not seek to construe the word “and” (as in “washing . . . and 

eluting”). Indeed, Amgen is so confident of this point, it did not even respond to Sandoz’s 

argument.

As an initial matter, Sandoz has not waived its right to seek construction of this phrase or 

to argue the claim has an implied order of steps. “As a general rule, unless the steps of a method 

claim actually recite an order, the steps are not ordinarily construed to require one.” Mformation 

Techs., Inc. v. Research in Motion Ltd., 764 F.3d 1392, 1398 (Fed. Cir. 2014) (internal quotation 

marks omitted). A claim may have a required order of steps, however, when “as a matter of logic 

or grammar, [the claim] requires that the steps be performed in the order written, or the 

specification directly or implicitly requires an order of steps.” Id. (internal quotation marks 

omitted). Thus, by designating “eluting the protein from the separation matrix” for construction, 

Sandoz adequately notified Amgen of its intent to seek construction and limited the number of 

terms to be construed to ten, as required by the local patent rules. See Local Patent Rule 4-1(b).

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The specification teaches, “[a]fter the separation matrix with which the protein has 

associated has been washed, the protein of interest is eluted using an appropriate solution.” ’878 

Patent at 15:60-62. It further explains that the wash buffer may be comprised of any number of 

components so long as “[t]he pH range is chosen to optimize the chromatography conditions,

preserve protein binding, and to retain the desired characteristics of the protein of interest.” ’878 

Patent at 15:55-57 (emphasis added). Thus, the proteins and separation matrix should remain 

associated during the washing process. In contrast, elution involves cleaving the protein from the 

matrix with “a solution that interferes with the binding of the absorbent component of the 

separation matrix to the protein, for example by disrupting the interactions between Protein A and 

the Fc region of a protein of interest.” ’878 Patent at 15:65-16:2 (emphasis added). Accordingly, 

the specification discloses a natural, logical order of steps. If the washing and eluting steps 

occurred simultaneously, the protein captured by the separation matrix could once again comingle 

with the contaminants and components to be washed away. In light of the fact, Amgen has not 

offered any reasons to believe the claim does not imply a natural order, the construction of the 

phrase will make clear the step of “eluting the protein from the separation matrix” occurs after the 

step of “washing the separation matrix.” 

As discussed above, the method claim 7 describes is not limited to the “expressed protein” 

or the “protein of interest.” Accordingly, the protein eluted from the separation matrix is “the 

purified protein.” After all, if elution is the final step of the purification process, the resulting 

protein is “purified.” Thus, the phrase “eluting the protein from the separation matrix” shall mean 

“applying a solution that reverses the binding of the purified protein to the separation matrix.” 

V. CONCLUSION

The disputed claim terms of the patents-in-suit are construed as set forth as follows:

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’427 Claim Term Construction

1.

“hematopoietic stem cell mobilizingeffective amount of G-CSF”An amount of G-CSF effective to 

mobilize hematopoietic stem cells.

2.

“A method of treating a disease requiring 

peripheral stem cell transplantation in a 

patient in need of such treatment”

The preamble limits the scope of the 

claim.

In the practice of the method of treating a 

disease, a patient receives a transplant of 

peripheral stem cells.

3.

“disease treating-effective amount of at 

least one chemotherapeutic agent”

An amount sufficient to treat a disease for 

which at least one chemotherapeutic 

agent is prescribed.

4.

“chemotherapeutic agent” Exogenous substance suited and used to 

damage or destroy microorganisms, 

parasites, or tumor cells.

5.

“comprising administering . . . G-CSF; 

and thereafter administering . . . at least 

one chemotherapeutic agent”

The word “comprising” means “including 

but not limited to,” and allows for 

additional steps before, in between, and 

after the steps recited in the claim.

In the practice of the method, at least one 

administration of G-CSF must occur 

before at least one administration of a 

chemotherapeutic agent.

6.

“opens the endothelial barrier of the 

patient to render the endothelial barrier 

permeable for stem cells”

Disrupts the bone marrow endothelial 

barrier to facilitate permeability of the 

endothelial barrier for stem cells.

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’878 Claim Term Construction

7.

“directly applying the refold solution to a 

separation matrix”

Applying the refold solution to a 

separation matrix without removing 

components of or diluting the refold 

solution.

8.

“under conditions suitable for the protein 

to associate with the matrix”

Under conditions suitable for the 

protein to be purified to bind to the 

matrix.

9.

“washing the separation matrix” Applying a solution to remove unbound 

protein, lysate, impurities, and 

unwanted components of the refold 

solution from the separation matrix 

while preserving binding of the 

expressed protein.

10.

“eluting the protein from the separation 

matrix”

Applying a solution that reverses the 

binding of the purified protein to the 

separation matrix. 

This step must occur after the step of 

“washing the separation matrix.”

A further Case Management Conference shall be held on September 15, 2016, at 10:00 

a.m. in Courtroom 3, 17th Floor, United States Courthouse, 450 Golden Gate Avenue, San 

Francisco, California. The parties shall file a Joint Case Management Statement at least one week 

prior to the Conference.

IT IS SO ORDERED.

Dated: August 4, 2016

______________________________________

RICHARD SEEBORG

United States District Judge

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