Office Action 1: Non-Final Rejection (2022-07-18)
Rejection types: 103 - Obviousness, 112 - Written Description/Enablement

CLAIMS:
Amendments to the Claims:

This listing of claims will replace all prior versions, and listings of claims in the application:

Listing of Claims:

1\. (Original) An antibody-drug conjugate pharmaceutical preparation, wherein the preparation comprises:

(a) antibody-drug conjugates with a structure as shown in formula I:
mAb-(L-D)n I wherein, mAb represents a recombinant anti-CD20 monoclonal antibody, which is rituximab or a biosimilar thereof;

D represents a small molecule toxin, which is one or more monomethyl auristatin;

L is a linker connecting the antibody and the small molecule toxin;

n is the average number of the small molecule toxins conjugated to the antibody;

and n is an integer or non-integer of 4.2 + 1; and

"-" is a bond; and

(b) a carrier or excipient.

2\. (Original) The antibody-drug conjugate pharmaceutical preparation of claim 1, wherein D is monomethyl auristatin-E (MMAE), monomethyl auristatin-D (MMAD), monomethyl auristatin-F (MMAF), or a combination thereof.

3\. (Original) The antibody-drug conjugate pharmaceutical preparation of claim 1, wherein L is maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl.

4\. (Original) The antibody-drug conjugate pharmaceutical preparation of claim 2 1, wherein the structure of the antibody-drug conjugate is shown as the following formula:
SVG {EMBED HERE} 1.45 6.61

5\. (Original) The antibody-drug conjugate pharmaceutical preparation of claim 1, wherein the preparation is an injection.

6\. (Original) The antibody-drug conjugate pharmaceutical preparation of claim 1, wherein the preparation is a solution or a lyophilized agent.

7\. (Original) The antibody-drug conjugate pharmaceutical preparation of claim 1, wherein the carrier or excipient is selected from the group consisting of a pH buffer, an osmotic pressure regulator, a lyophilized powder excipient, a protein protecting agent, a solubilizer, and water for injection.

8\. (Original) The antibody-drug conjugate pharmaceutical preparation of claim 1, wherein the preparation method for the antibody-drug conjugate comprises the following steps:

(1) performing a reduction reaction between the recombinant anti-CD20 monoclonal antibody and a reducing agent, thereby obtaining a reaction system comprising a reduced recombinant anti-CD20 monoclonal antibody; and the molar ratio of the monoclonal antibody to the reducing agent is 1: 2.9 to 1: 3.1; and

(2) performing a coupling reaction between the reaction system of step (1) and a solution of a small molecule toxin in acetonitrile and water to form the antibody-drug conjugates according to claim 1; and the molar ratio of the monoclonal antibody in step (1) to the small molecule toxin is 1: 7.0 to 1: 8.0.

9\. (Currently Amended) Use of the antibody-drug conjugate pharmaceutical 2 preparation according to claim 1 for preparing anti-tumor drugs.

10\. (Currently Amended) A non-therapeutic method for inhibiting tumor cells, wherein the method comprises the step of adding the antibody-drug conjugate pharmaceutical preparation according to claim 1 to a tumor cell-containing 4 system.
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OFFICE ACTION:
DETAILED ACTION
Notice of Pre-AIA  or AIA  Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA  35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-3, 5-10 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA  35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The rejected claims cover, inter alia, anti-CD20 ADC’s.
To satisfy the written-description requirement, the specification must describe every element of the claimed invention in sufficient detail so that one of ordinary skill in the art would recognize that the inventor possessed the claimed invention at the time of filing. Vas-Cath, 935 F.3d at 1563; see also Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572 (Fed. Cir. 1997) (patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention”); In re Gosteli, 872 F.2d 1008, 1012 (Fed. Cir. 1989) (“the description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed”).
With regard to the recited genus of anti-CD20 ADC’s the following applies:
Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 94 USPQ2d 1161 (Fed. Cir. 2010) states that “...a generic claim may define the boundaries of a vast genus of chemical compounds...the question may still remain whether the specification, including the original claim language, demonstrates that the applicant invented species sufficient to support a claim to a genus”. See page 1171.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
See also Fujikawa v. Wattanasin, 93 F.3d 1559, 1571, 39 USPQ2d 1895, 1905 (Fed. Cir. 1996) (a “laundry list” disclosure of every possible moiety does not constitute a written description of every species in a genus because it would not “reasonably lead” those skilled in the art to any particular species.
Amgen, Inc. v. Chugai Pharmaceutical Co., Ltd., 927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) states that “it is well established in our law that conception of a chemical compound requires that the inventor be able to define it so as to distinguish it from other materials, and to describe how to obtain it”.
A description of a genus may be achieved by means of a recitation of a representative number of species falling within the scope of the genus or structural features common to the members of the genus, which features constitute a substantial portion of the genus, so that one of skill in the art can “visualize or recognize” the members of the genus (Emphasis added). Regents of the University of California v. Eli Lilly & Co., 119 F3d 1559, 1569, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997).
A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure “indicates that the patentee has invented species sufficient to constitute the gen[us].” See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004)(“[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.”). “A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when ... the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.” In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004).
In Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412), the court held that a generic statement which defines a genus of nucleic acids by only their functional activity does not provide an adequate written description of the genus. The court indicated that, while applicants are not required to disclose every species encompassed by a genus, the description of the genus is achieved by the recitation of a representative number of species falling within the scope of the claimed genus. At section B(i), the court states, An adequate written description of a DNA ... requires a precise definition, such as by structure, formula, chemical name, or physical properties, not a mere wish or plan for obtaining the claimed chemical invention.
Courts have stated that “[i]n claims involving [non-genetic] chemical materials, generic formulae usually indicate with specificity what the generic claims encompass. One skilled in the art can distinguish such a formula from others and can identify many of the species that the claims encompass. Accordingly, such a formula is normally an adequate description of the claimed genus.” Regents of the University of California v. Eli Lilly & Co., 119 F.3d 1559, 1568 (Fed. Cir. 1997), cert. denied, 523 U.S. 1089 (1998). (emphasis added).   There is no such specificity here, nor could one skilled in the art identify any particular compound encompassed by the claims. To the contrary, the specification states that the claimed compounds are derived from the recited substituents.
Here, Applicant desires patent protection for anti-CD20 ADC’s.  However, in view of the above, the specification does not provide adequate written description of the claimed genus of anti-CD20 ADC’s. Specifically, Applicant fails to disclose any other ADC’s, besides those covered by the formulas in the specification and claims, and in relation to the above, these disclosed species or subgeni do not represent the substantial variety covered by the genus of anti-CD20 ADC’s.
With regard to the functional definition of anti-CD20 ADC, the specification does not clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed (see Vas-Cath at page 1116) because the specification contains almost no information by which a person of ordinary skill in the art would understand that the inventors possessed the all of the recited compounds. At best, it simply indicates that one should test an infinite number of conjugates to see if the compounds can perform the required function. see In re ’318 Patent Infringement Litigation, 583 F.3d 1317, 1327 (Fed. Cir. 2009) (“[A]t the end of the day, the specification, even read in light of the knowledge of those skilled in the art, does no more than state a hypothesis and propose testing to determine the accuracy of that hypothesis. That is not sufficient.”).
The Examiner acknowledges that a working example or exemplified embodiment is not necessarily a requirement for description. However, where a generic claim term is present in a claim, as in the present application, and defined only by functional characteristics, the specification must convey enough information, e.g., via sufficient representative examples, to indicate invention of species sufficient to constitute the genus. Enzo Biochem, Inc. v. Gen-Probe Inc., 323 F.3d 956, 967 2 (Fed. Cir. 2002). The written description requirement “requires a description of an invention, not an indication of a result that one might achieve if one made that invention.” Regents of the University of California v. Eli Lilly & Co., 119 F.3d 1559, 1568 (Fed. Cir. 1997); see also Novozymes A/S v. DuPont Nutrition Biosciences APS, 723 F.3d 1336, 1350 (Fed. Cir. 2013) (“A patent...‘is not a reward for the search, but compensation for its successful conclusion.’ ... For that reason, the written description requirement prohibits a patentee from ‘leaving it to the ... industry to complete an unfinished invention.’” (citations omitted)).
Accordingly, the specification lacks adequate written description for the recited anti-CD20 ADC’s.
The following is a quotation of 35 U.S.C. 112(b):
(b)  CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-10 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA  35 U.S.C. 112, the applicant), regards as the invention.
The structural criteria of a rituximab “biosimilar” is not defined.
Claim 9 recites a use of the instant ADC without any of the required preparation steps.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim(s) 1-6, 8-10 are rejected under 35 U.S.C. 103 as being unpatentable over Jain et al., Pharm Res (2015) 32:3526–3540 (Jain) in view of U.S. Publication No. 20050180972 based on an application by Wahl et al. (Wahl).
Jain teaches VAL-CIT-MMAE antibody conjugates:
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Jain teaches that these ADC’s with the recited drug-antibody-ratio (DAR) are known:
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The recited preparation, such as those suitable for injection are taught, see paragraphs 0242+.
Jain may fail to explicitly teach ADC’s with an antiCD-20 antibody.  However, it is for that proposition that the examiner joins Wahl.  Specifically, Wahl teaches that conjugating mc-vc-PABC-MMAE to anti-CD20 antibodies, like rituximab, was common for cancer therapy:
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Wahl also discloses the recited excipients suitable for these ADC.s see paragraphs 247+.
In this way, those of ordinary skill could have applied anti-CD20 antibodies in the manner required and in a predictable fashion for the purposes of providing the recited ADC’s.  As outlined above, Jain teaches that the recited ADC’s with the recited drug-antibody-ratio (DAR) are common, such as mc-vc-PABC-MMAE.  Wahl is added for the proposition that anti-CD-20 antibodies are applicable to these ADC’s.  Specifically, Wahl teaches that the particular known technique of conjugating anti-CD-20 ADC’s with mc-vc-PABC-MMAE was recognized as part of the ordinary capabilities of one skilled in the art.  In this manner, those of ordinary skill would have recognized that applying the known technique to anti-CD-20 antibodies, like rituximab, would have yielded predictable results.  Accordingly, using anti-CD20 antibodies with mc-vc-PABC-MMAE would have been prima facie obvious.
Conclusion


NEXT OFFICE ACTION: DETAILED ACTION
Notice of Pre-AIA  or AIA  Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The rejection under section 112(a) is withdrawn in view of Applicant’s Amendments and remarks in connection with this ground of rejection.
The rejections under section 112(b) is maintained, below.  Any new grounds of rejection under this section are necessitated by Applicant’s amendments.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b)  CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 5-7, 9, 11-22 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA  35 U.S.C. 112, the applicant), regards as the invention.
The structural criteria of a rituximab “biosimilar” remains undefined.  Applicant argues that the antibody made in the specification (TRS001) is identical to rituximab and that based on this antibody a biosimilar antibody is a monoclonal antibody agent developed utilizing the sequence of rituximab.  However, as Applicant indicated, TRS001 is the same antibody as rituximab.  the specification and claims do not define any other parameters for “biosimilar” other than it is the same antibody as rituximab.  Therefore, it is unclear which antibodies, other than rituximab, Applicant intends to cover by the term “biosimilar”.
Claim 9 still recites a utilizing the instant ADC without any of the required preparation steps for anti-tumor drugs.
The prior art rejection is withdrawn in favor of the following new grounds of rejection under this section, which are necessitated by Applicant’s amendments.
Omission of claim 7 from the previous rejection under this section was an obvious error since the rejection explicitly states that “[t]he recited preparation, such as those suitable for injection are taught, see paragraphs 0242+.” which is covered in claim 7.  The rejection also stated that Wahl also discloses the recited excipients suitable for these ADC.s see paragraphs 247+. Therefore, the rejection of claim 7 is included below:
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim(s) 1, 5-7, 9, 11-22 are rejected under 35 U.S.C. 103 as being unpatentable over Jain et al., Pharm Res (2015) 32:3526–3540 (Jain);
in view of U.S. Publication No. 20050180972 based on an application by Wahl et al. (Wahl) and Chen et al., Determination of Drug-to-Antibody Ratio for Antibody-Drug Conjugates Purified from Serum, Agilent Technologies, pp. 1-9, 2016 (Agilent).
Jain teaches VAL-CIT-MMAE antibody conjugates:
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Jain teaches that these ADC’s with the recited drug-antibody-ratio (DAR) are known:
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The recited preparation, such as those suitable for injection are taught, see paragraphs 0242+.
Jain may fail to explicitly teach ADC’s with an anti-CD-20 antibody.  However, it is for that proposition that the examiner joins Wahl.  Specifically, Wahl teaches that conjugating mc-vc-PABC-MMAE to anti-CD20 antibodies, like rituximab, was common for cancer therapy:
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Wahl also discloses the recited excipients suitable for these ADC.s see paragraphs 247+.
In this way, those of ordinary skill could have applied anti-CD20 antibodies in the manner required and in a predictable fashion for the purposes of providing the recited ADC’s.  As outlined above, Jain teaches that the recited ADC’s with the recited drug-antibody-ratio (DAR) are common, such as mc-vc-PABC-MMAE.  Wahl is added for the proposition that anti-CD-20 antibodies are applicable to these ADC’s.  Specifically, Wahl teaches that the particular known technique of conjugating anti-CD-20 ADC’s with mc-vc-PABC-MMAE was recognized as part of the ordinary capabilities of one skilled in the art.  In this manner, those of ordinary skill would have recognized that applying the known technique to anti-CD-20 antibodies, like rituximab, would have yielded predictable results.  Accordingly, using anti-CD20 antibodies with mc-vc-PABC-MMAE would have been prima facie obvious.
Applicant argues that Wahl does not teach or suggest rituximab or a biosimilar thereof conjugating with monomethyl auristatin-E with the average number of the small molecule toxins conjugated to the antibody of 4.2 + 1. Applicant also argues that Wahl provides the drug- antibody ratio of Rituxan-vcMMAE is 7. (See Wahl, table 1).
However, it is understood that the DAR in the table is an average DAR.  Indeed, those of ordinary skill would understand that preparation of the Rituximab vcMMAE in Wahl would produce a number of ADC’s with different DAR’s, including 4.
Nonetheless, there are a limited and finite number of DAR’s for a cysteine-bound antibody-drug conjugate (ADC), around 8. The prior art demonstrates that optimization of the DAR is a critical part of ADC development, since the DAR value affects the efficacy of the drug, as low drug loading reduces the potency, while high drug loading can negatively affect pharmacokinetics (PK)1 and toxicity. At the time the invention was made, easy, accurate and reproducible DAR calculation of ADC’s was within the purview of those of ordinary skill, see Agilent:
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In this manner, it would have been obvious to one having ordinary skill in the art at the time of applicant’s invention to have prepared ADC’s within the recited DAR with a reasonable expectation that the resulting ADC would be useful in treating cancer. In this connection, it is well-settled that cysteine-conjugated ADC’s with a DAR from 1-8 are well within the purview of those of ordinary skill (see above); and it would have been obvious to one of ordinary skill in the art at the time the invention was made to have chosen from this finite number of DAR options with a reasonable expectation of success of producing an ADC with a functional DAR.
Specifically, the DAR pf cysteine-bound ADC’s is optimizable.  It is well within the skill of the artisan to try any of the 1-8 DAR targets. As outlined above, a DAR value affects the efficacy of the drug, as low drug loading reduces the potency, while high drug loading can negatively affect pharmacokinetics (PK)1 and toxicity. Here, a skilled chemist at the time would simply make the known ADC’s of the known 8 DAR’s. Indeed, it would have been part and parcel to make the different DAR’s to find one that is pharmaceutically acceptable. See Agilent: (“The DAR is a critical quality attribute of an ADC that is optimized and closely monitored during ADC development, as it can affect efficacy and toxicity.”)  Therefore, the applied references provide ample reason to make the recited ADC’s with a DAR in the recited range.
With regard to any unpredictability associated with the DAR’s, the notion that unpredictability confers patentability in cases of DAR’s of known ADC’s should be disregarded since a rule of law equating unpredictability to patentability, applied in this case, would mean that any new ADC based on a different DAR would be separately patentable, simply because the formation and properties of each ADC must be verified through testing. This cannot be the proper standard since the expectation of success need only be reasonable, not absolute.
Here, the references provide the reasonable expectation of success. Namely, the references demonstrate the reasonable expectation of success since the references sufficiently characterize the instant ADC’s including the required heavy and light chains (i.e., Rituximab), conjugated to MMAE via a val/cit linker (see Jain and Wahl). Again, the expectation of success need only be reasonable, as it is here, and not absolute, (“obviousness does not require absolute predictability, only a reasonable expectation of success, i.e., a reasonable expectation of obtaining similar properties. See, e.g., In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988).”).
With regard to any alleged unexpected property possessed by those ADC’s with a DAR within the claimed range, it is error to assume that any superior property is unexpected, especially in the instant case, where the pharmacodynamic and pharmacokinetic properties of different DAR’s are not predictable. In this case, given the range of 8 possible DAR’s, one skilled in the art would expect different DAR’s to provide ADC’s having a range of properties, some of which would be superior, and some of which would be inferior.
Rather, Applicant has conducted a common optimization of the known DAR’s to produce the claimed ADC, which is routine. Specifically, Applicant engaged in routine, verification testing to optimize selection of one of several known and clearly suggested DAR’s to prepare a pharmaceutically-acceptable conjugate. In this regard, creating a “product or process that is more desirable, for example because it is stronger, cheaper, cleaner, faster, lighter, smaller, more durable, or more efficient . . . to enhance commercial opportunities . . . is universal—and even common-sensical.” see DyStar Textilfarben GmbH v. C.H. Patrick Co., 464 F.3d 1356 at 1368.
Finally, the claims recite product-by-process limitations.  Applicant has not demonstrated how these limitations distinguish the recited ADC, see MPEP 2113 (“[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process. In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985)”).
Therefore, the recited ADC’s with the recited DAR is obvious, within the meaning of section 103.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action.  Accordingly, THIS ACTION IS MADE FINAL.  See MPEP § 706.07(a).  Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action.  In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action.  In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
Conclusion

CITED REFERENCE SUMMARIES: Ref US20050180972A1: Claims:
An anti-CD20 antibody-cytotoxic agent conjugate, wherein the cytotoxic agent of the anti-CD20 antibody-cytotoxic agent conjugate has an IC 50 of between 40-fold and 4,000-fold less than the IC 50 of doxorubicin, with the proviso that the cytotoxic agent is not a radioisotope or a toxin, and wherein the IC 50 of each of the cytotoxic agent and doxorubicin is measured by a method comprising: (a) culturing one or more CD20-expressing cell populations in the presence of one or more concentrations of the cytotoxic agent for a 72-to 96-hour period; (b) culturing one or more CD20-expressing cell populations in the presence of one or more concentrations of doxorubicin for a 72- to 96-hour period; and (c) identifying a concentration of the cytotoxic agent and doxorubicin, respectively, at which 50% fewer cells in the CD20-expressing cell populations of steps (a) and (b), respectively, are viable at the end of the period relative to a CD20-expressing cell population cultured in the absence of the cytotoxic agent and doxorubicin, wherein the CD20-expressing cell populations of steps (a), (b) and (c) are of the same cell type and are cultured under the same conditions, and wherein the concentration of the cytotoxic agent and doxorubicin identified in step (c) is the IC 50 of the cytotoxic agent and doxorubicin, respectively.
(a) culturing one or more CD20-expressing cell populations in the presence of one or more concentrations of the cytotoxic agent for a 72-to 96-hour period;
(b) culturing one or more CD20-expressing cell populations in the presence of one or more concentrations of doxorubicin for a 72- to 96-hour period; and
(c) identifying a concentration of the cytotoxic agent and doxorubicin, respectively, at which 50% fewer cells in the CD20-expressing cell populations of steps (a) and (b), respectively, are viable at the end of the period relative to a CD20-expressing cell population cultured in the absence of the cytotoxic agent and doxorubicin,
wherein the CD20-expressing cell populations of steps (a), (b) and (c) are of the same cell type and are cultured under the same conditions,
and wherein the concentration of the cytotoxic agent and doxorubicin identified in step (c) is the IC 50 of the cytotoxic agent and doxorubicin, respectively.
- 5 . (canceled)
An anti-CD20 antibody-cytotoxic agent conjugate, wherein the anti-CD20 antibody-cytotoxic agent conjugate has an IC 50 of between 40-fold and 4,000-fold less than the IC 50 of an anti-CD20 antibody-doxorubicin conjugate, with the proviso that the cytotoxic agent is not a radioisotope or a toxin, wherein the anti-CD20 antibody-cytotoxic agent conjugate and the anti-CD20 antibody-doxorubicin conjugate comprise the same anti-CD20 antibody, and wherein the IC 50 of each of the anti-CD20 antibody-cytotoxic agent conjugate and the anti-CD20 antibody-doxorubicin conjugate is measured by a method comprising: (a) culturing one or more CD20-expressing cell populations in the presence of one or more concentrations of the anti-CD20 antibody-cytotoxic agent conjugate for a 72- to 96-hour period; (b) culturing one or more CD20-expressing cell populations in the presence of one or more concentrations of the anti-CD20 antibody-doxorubicin conjugate for a 72- to 96-hour period; and (c) identifying a concentration of the anti-CD20 antibody-cytotoxic agent conjugate and the anti-CD20 antibody-doxorubicin conjugate, respectively, at which 50% fewer cells in the CD20-expressing cell populations of steps (a) and (b), respectively, are viable at the end of the period relative to a CD20-expressing cell population type cultured in the absence of the anti-CD20 antibody-cytotoxic agent conjugate and the anti-CD20 antibody-doxorubicin conjugate, wherein the CD20-expressing cell populations of steps (a), (b) and (c) are of the same cell type and are cultured under the same conditions, and wherein the concentration of the anti-CD20 antibody-cytotoxic agent conjugate and the anti-CD20 antibody-doxorubicin conjugate identified in step (c) is the IC 50 of the anti-CD20 antibody-cytotoxic agent conjugate and the anti-CD20 antibody-doxorubicin conjugate, respectively.
(a) culturing one or more CD20-expressing cell populations in the presence of one or more concentrations of the anti-CD20 antibody-cytotoxic agent conjugate for a 72- to 96-hour period;
(b) culturing one or more CD20-expressing cell populations in the presence of one or more concentrations of the anti-CD20 antibody-doxorubicin conjugate for a 72- to 96-hour period; and
(c) identifying a concentration of the anti-CD20 antibody-cytotoxic agent conjugate and the anti-CD20 antibody-doxorubicin conjugate, respectively, at which 50% fewer cells in the CD20-expressing cell populations of steps (a) and (b), respectively, are viable at the end of the period relative to a CD20-expressing cell population type cultured in the absence of the anti-CD20 antibody-cytotoxic agent conjugate and the anti-CD20 antibody-doxorubicin conjugate,
and wherein the concentration of the anti-CD20 antibody-cytotoxic agent conjugate and the anti-CD20 antibody-doxorubicin conjugate identified in step (c) is the IC 50 of the anti-CD20 antibody-cytotoxic agent conjugate and the anti-CD20 antibody-doxorubicin conjugate, respectively.
- 11 . (canceled)
An anti-CD20 antibody-cytotoxic agent conjugate, wherein the conjugate has a rate of accumulation in a CD20-expressing cell that is between 20-fold and 5,000-fold greater than the rate of accumulation of an unconjugated form of the anti-CD20 antibody in the CD20-expressing cell, wherein the rates of accumulation of the conjugate and of the unconjugated form of the antibody are measured by a method comprising: (a) culturing a population of the CD20-expressing cell with the conjugate; (b) culturing a population of the CD20-expressing cell with the unconjugated antibody, wherein the populations of steps (a) and (b) are cultured under the same conditions; and (c) measuring the amount of the conjugate and unconjugated antibody accumulated in the populations of steps (a) and (b), respectively.
(a) culturing a population of the CD20-expressing cell with the conjugate;
(b) culturing a population of the CD20-expressing cell with the unconjugated antibody, wherein the populations of steps (a) and (b) are cultured under the same conditions; and
(c) measuring the amount of the conjugate and unconjugated antibody accumulated in the populations of steps (a) and (b), respectively.
- 17 . (canceled)
An anti-CD20 antibody-cytotoxic agent conjugate, wherein the conjugate has a rate of accumulation in a CD20-expressing cell that is between 20-fold and 5,000-fold greater than the rate of accumulation of an anti-CD20 antibody-doxorubicin conjugate in a CD20-expressing cell of the same cell type, wherein the anti-CD20 antibody-cytotoxic agent conjugate and the anti-CD20 antibody-doxorubicin conjugate comprise the same anti-CD20 antibody, and wherein the rates of accumulation of the anti-CD20 antibody-cytotoxic agent conjugate and of the anti-CD20 antibody-doxorubicin conjugate are measured by a method comprising: (a) culturing a population of the CD20-expressing cell with the anti-CD20 antibody-cytotoxic agent conjugate; (b) culturing a population of the CD20-expressing cell with the anti-CD20 antibody-doxorubicin conjugate, wherein the populations of steps (a) and (b) are cultured under the same conditions; and (c) measuring the amount of the anti-CD20 antibody-cytotoxic agent conjugate and anti-CD20 antibody-doxorubicin conjugate accumulated in the populations of steps (a) and (b), respectively.
(a) culturing a population of the CD20-expressing cell with the anti-CD20 antibody-cytotoxic agent conjugate;
(b) culturing a population of the CD20-expressing cell with the anti-CD20 antibody-doxorubicin conjugate, wherein the populations of steps (a) and (b) are cultured under the same conditions; and
(c) measuring the amount of the anti-CD20 antibody-cytotoxic agent conjugate and anti-CD20 antibody-doxorubicin conjugate accumulated in the populations of steps (a) and (b), respectively.
- 21 . (canceled)
An anti-CD20 antibody-cytotoxic agent conjugate, wherein the conjugate exhibits an accumulation in a non-peripheral region inside a CD20-expressing cell that is between 1.5-fold and 5,000-fold greater than the accumulation of an unconjugated form of the anti-CD20 antibody in the CD20-expressing cell, wherein the accumulation of the conjugate and of the unconjugated form of the antibody are measured by a method comprising: (a) culturing a population of the CD20-expressing cell with the conjugate; (b) culturing a population of the CD20-expressing cell with the unconjugated form of the anti-CD20 antibody; and (c) detecting by confocal fluorescence microscopy localization of the conjugate and the unconjugated form of the anti-CD20 antibody in the populations of steps (a) and (b), respectively, wherein the populations of steps (a) and (b) are cultured under the same conditions and for the same period of time, and wherein the conjugate exhibits an accumulation in the CD20-expressing cell that is between 1.5-fold and 5,000-fold greater than the accumulation of the unconjugated form of the anti-CD20 antibody in the CD20-expressing cell if: (i) between 1.5-fold and 5,000-fold as many cells of the population of step (a) contain a detectable amount of the conjugate in a non-peripheral region as the number of cells of the population of step (b) contain the unconjugated form of the antibody in a non-peripheral region; or (ii) the accumulation of the conjugate in a non-peripheral region of the majority of CD20-expressing cells of the population of step (a) is between 1.5-fold and 5,000-fold greater than the accumulation of the unconjugated form of the anti-CD20 antibody in the majority of CD20-expressing cells of the population of step (b).
(b) culturing a population of the CD20-expressing cell with the unconjugated form of the anti-CD20 antibody; and
(c) detecting by confocal fluorescence microscopy localization of the conjugate and the unconjugated form of the anti-CD20 antibody in the populations of steps (a) and (b), respectively,
wherein the populations of steps (a) and (b) are cultured under the same conditions and for the same period of time, and wherein the conjugate exhibits an accumulation in the CD20-expressing cell that is between 1.5-fold and 5,000-fold greater than the accumulation of the unconjugated form of the anti-CD20 antibody in the CD20-expressing cell if:
(i) between 1.5-fold and 5,000-fold as many cells of the population of step (a) contain a detectable amount of the conjugate in a non-peripheral region as the number of cells of the population of step (b) contain the unconjugated form of the antibody in a non-peripheral region; or
(ii) the accumulation of the conjugate in a non-peripheral region of the majority of CD20-expressing cells of the population of step (a) is between 1.5-fold and 5,000-fold greater than the accumulation of the unconjugated form of the anti-CD20 antibody in the majority of CD20-expressing cells of the population of step (b).
- 25 . (canceled)
An anti-CD20 antibody-cytotoxic agent conjugate, wherein the conjugate exhibits an accumulation in a non-peripheral region inside a CD20-expressing cell that is between 1.5-fold and 5,000-fold greater than the accumulation of an anti-CD20 antibody-doxorubicin conjugate, wherein the anti-CD20 antibody-cytotoxic agent conjugate and the anti-CD20 antibody-doxorubicin conjugate comprise the same anti-CD20 antibody, in the CD20-expressing cell, wherein the accumulation of the conjugate and of the anti-CD20 antibody-doxorubicin conjugate are measured by a method comprising: (a) culturing a population of the CD20-expressing cell with the conjugate; (b) culturing a population of the CD20-expressing cell with the anti-CD20 antibody-doxorubicin conjugate; and (c) detecting by confocal fluorescence microscopy localization of the conjugate and the anti-CD20 antibody-doxorubicin conjugate in the populations of steps (a) and (b), respectively, wherein the populations of steps (a) and (b) are cultured under the same conditions and for the same period of time, and wherein the conjugate exhibits an accumulation in the CD20-expressing cell that is between 1.5-fold and 5,000-fold greater than the accumulation of the anti-CD20 antibody-doxorubicin conjugate in the CD20-expressing cell if: (i) between 1.5-fold and 5,000-fold as many cells of the population of step (a) contain a detectable amount of the conjugate in a non-peripheral region as the number of cells of the population of step (b) contain the anti-CD20 antibody-doxorubicin conjugate in a non-peripheral region; or (ii) the accumulation of the conjugate in a non-peripheral region of the majority of CD20-expressing cells of the population of step (a) is between 1.5-fold and 5,000-fold greater than the accumulation of the anti-CD20 antibody-doxorubicin conjugate in the majority of CD20-expressing cells of the population of step (b).
(b) culturing a population of the CD20-expressing cell with the anti-CD20 antibody-doxorubicin conjugate; and
(c) detecting by confocal fluorescence microscopy localization of the conjugate and the anti-CD20 antibody-doxorubicin conjugate in the populations of steps (a) and (b), respectively,
wherein the populations of steps (a) and (b) are cultured under the same conditions and for the same period of time, and wherein the conjugate exhibits an accumulation in the CD20-expressing cell that is between 1.5-fold and 5,000-fold greater than the accumulation of the anti-CD20 antibody-doxorubicin conjugate in the CD20-expressing cell if:
(i) between 1.5-fold and 5,000-fold as many cells of the population of step (a) contain a detectable amount of the conjugate in a non-peripheral region as the number of cells of the population of step (b) contain the anti-CD20 antibody-doxorubicin conjugate in a non-peripheral region; or
(ii) the accumulation of the conjugate in a non-peripheral region of the majority of CD20-expressing cells of the population of step (a) is between 1.5-fold and 5,000-fold greater than the accumulation of the anti-CD20 antibody-doxorubicin conjugate in the majority of CD20-expressing cells of the population of step (b).
- 64 . (canceled)
A pharmaceutical composition comprising an anti-CD20 antibody-cytotoxic agent conjugate, wherein the cytotoxic agent of the anti-CD20 antibody-cytotoxic agent conjugate has an IC 50 of between 40-fold and 4,000-fold less than the IC 50 of doxorubicin, with the proviso that the cytotoxic agent is not a radioisotope or a toxin, and wherein the IC 50 of each of the cytotoxic agent and doxorubicin is measured by a method comprising: (a) culturing one or more CD20-expressing cell populations in the presence of one or more concentrations of the cytotoxic agent for a 72-to 96-hour period; (b) culturing one or more CD20-expressing cell populations in the presence of one or more concentrations of doxorubicin for a 72- to 96-hour period; and (c) identifying a concentration of the cytotoxic agent and doxorubicin, respectively, at which 50% fewer cells in the CD20-expressing cell populations of steps (a) and (b), respectively, are viable at the end of the period relative to a CD20-expressing cell population cultured in the absence of the cytotoxic agent and doxorubicin, wherein the CD20-expressing cell populations of steps (a), (b) and (c) are of the same cell type and are cultured under the same conditions, and wherein the concentration of the cytotoxic agent and doxorubicin identified in step (c) is the IC 50 of the cytotoxic agent and doxorubicin, respectively.
A pharmaceutical composition comprising an anti-CD20 antibody-cytotoxic agent conjugate, wherein the anti-CD20 antibody-cytotoxic agent conjugate has an IC 50 of between 40-fold and 4,000-fold less than the IC 50 of an anti-CD20 antibody-doxorubicin conjugate, with the proviso that the cytotoxic agent is not a radioisotope or a toxin, wherein the anti-CD20 antibody-cytotoxic agent conjugate and the anti-CD20 antibody-doxorubicin conjugate comprise the same anti-CD20 antibody, and wherein the IC 50 of each of the anti-CD20 antibody-cytotoxic agent conjugate and the anti-CD20 antibody-doxorubicin conjugate is measured by a method comprising: (a) culturing one or more CD20-expressing cell populations in the presence of one or more concentrations of the anti-CD20 antibody-cytotoxic agent conjugate for a 72- to 96-hour period; (b) culturing one or more CD20-expressing cell populations in the presence of one or more concentrations of the anti-CD20 antibody-doxorubicin conjugate for a 72- to 96-hour period; and (c) identifying a concentration of the anti-CD20 antibody-cytotoxic agent conjugate and the anti-CD20 antibody-doxorubicin conjugate, respectively, at which 50% fewer cells in the CD20-expressing cell populations of steps (a) and (b), respectively, are viable at the end of the period relative to a CD20-expressing cell population cultured in the absence of the anti-CD20 antibody-cytotoxic agent conjugate and the anti-CD20 antibody-doxorubicin conjugate, wherein the CD20-expressing cell populations of steps (a), (b) and (c) are of the same cell type and are cultured under the same conditions, and wherein the concentration of the anti-CD20 antibody-cytotoxic agent conjugate and the anti-CD20 antibody-doxorubicin conjugate identified in step (c) is the IC 50 of the anti-CD20 antibody-cytotoxic agent conjugate and the anti-CD20 antibody-doxorubicin conjugate, respectively.
(c) identifying a concentration of the anti-CD20 antibody-cytotoxic agent conjugate and the anti-CD20 antibody-doxorubicin conjugate, respectively, at which 50% fewer cells in the CD20-expressing cell populations of steps (a) and (b), respectively, are viable at the end of the period relative to a CD20-expressing cell population cultured in the absence of the anti-CD20 antibody-cytotoxic agent conjugate and the anti-CD20 antibody-doxorubicin conjugate,
A pharmaceutical composition comprising an anti-CD20 antibody-cytotoxic agent conjugate, wherein the conjugate has a rate of accumulation in a CD20-expressing cell that is between 20-fold and 5,000-fold greater than the rate of accumulation of an unconjugated form of the anti-CD20 antibody in the CD20-expressing cell, with the proviso that the cytotoxic agent is not a radioisotope or a toxin, wherein the rates of accumulation of the conjugate and of the unconjugated form of the antibody are measured by a method comprising: (a) culturing a population of the CD20-expressing cell with the conjugate; (b) culturing a population of the CD20-expressing cell with the unconjugated antibody, wherein the populations of steps (a) and (b) are cultured under the same conditions; and (c) measuring the amount of the conjugate and unconjugated antibody accumulated in the populations of steps (a) and (b), respectively.
A pharmaceutical composition comprising an anti-CD20 antibody-cytotoxic agent conjugate, wherein the conjugate has a rate of accumulation in a CD20-expressing cell that is between 20-fold and 5,000-fold greater than the rate of accumulation of an anti-CD20 antibody-doxorubicin conjugate in a CD20-expressing cell of the same cell type, with the proviso that the cytotoxic agent is not a radioisotope or a toxin, wherein the anti-CD20 antibody-cytotoxic agent conjugate and the anti-CD20 antibody-doxorubicin conjugate comprise the same anti-CD20 antibody, and wherein the rates of accumulation of the anti-CD20 antibody-cytotoxic agent conjugate and of the anti-CD20 antibody-doxorubicin conjugate are measured by a method comprising: (a) culturing a population of the CD20-expressing cell with the anti-CD20 antibody-cytotoxic agent conjugate; (b) culturing a population of the CD20-expressing cell with the anti-CD20 antibody-doxorubicin conjugate, wherein the populations of steps (a) and (b) a
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