Office Action 1: Non-Final Rejection (2023-10-20)
Rejection types: 112 - Written Description/Enablement, Double Patenting

CLAIMS:
What is claimed is:

1\. An injectable pharmaceutical formulation comprising:a) 25 mg/mL of a fully human anti-interferon gamma (IFNy) monoclonal antibody; and b) 1.55 mg/mL L-histidine, 3.14 mg/mL L-histidine monohydrochloride, monohydrate,
0.05 mg/mL Polysorbate 80, and 7.31 mg/mL sodium chloride (NaCl),wherein the pH is between 5.8 and 6.2, and
wherein the antibody comprises a variable heavy chain complementarity determining region 1 (VH CDR1) comprising the amino acid sequence of SEQ ID NO: 1;
a variable heavy chain complementarity determining region 2 (VH CDR2) comprising the amino acid sequence of SEQ ID NO: 2;
a variable heavy chain complementarity determining region 3 (VH CDR3) comprising the amino acid sequence of SEQ ID NO: 3;
a variable light chain complementarity determining region 1 (VL CDR1) comprising the amino acid sequence of SEQ ID NO: 4;
a variable light chain complementarity determining region 2 (VL CDR2) region comprising the amino acid sequence of SEQ ID NO: 5; and a variable light chain complementarity determining region 3 (VL CDR3) region comprising the amino acid sequence of SEQ ID NO: 6.

2\. The formulation of claim 1, wherein the antibody comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 47, and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 48.

3\. The unit dose vial of claim 1, wherein the antibody is solubilized in the solution such that the solution is clear, colorless, and without precipitate.

4\. A method of treating a condition in a human subject by administering the formulation of claim 1, wherein the condition is primary hemophagocytic lymphohistiocytosis (HLH) or secondary HLH.

5\. The method of claim 4, wherein the human subject is pediatric or adult.

6\. A unit dose vial comprising, 2 mL, 4mL, 10 mL or 20 mL of a fully human anti- interferon gamma (IFNy) monoclonal antibody solution suitable for injection,wherein the solution comprises 1.55 mg/mL L-histidine, 3.14 mg/mL L-histidine monohydrochloride, monohydrate, 0.05 mg/mL Polysorbate 80, and 7.31 mg/mL sodium chloride (NaCl),
wherein the pH of the solution is between 5.8 and 6.2,
wherein the concentration of antibody is at 25 mg/mL, and
wherein the antibody comprises:
a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 1;
a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 2;
a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 3;
a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 4;
a VL CDR2 region comprising the amino acid sequence of SEQ ID NO: 5; and a VL CDR3 region comprising the amino acid sequence of SEQ ID NO: 6.

7\. The unit dose vial of claim 6, wherein the antibody comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 47, and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 48.

8\. The unit dose vial of claim 6, wherein the antibody is solubilized in the solution such that the solution is clear, colorless, and without precipitate.

9\. A method of treating a condition in a human subject by administering the unit dose vial of claim 6, wherein the condition is primary hemophagocytic lymphohistiocytosis (HLH) or secondary HLH.

10\. The method of claim 9, wherein the human subject is pediatric or adult.

OFFICE 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 .
DETAILED ACTION
Applicant’s Track One request filed 10-5-23 is acknowledged.
Claims 1-10 are pending and under examination.
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.
Claims 6-10 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.  This is a new matter rejection.
MPEP § 2063.05 instructs:
The introduction of claim changes which involve narrowing the claims by introducing elements or limitations which are not supported by the as-filed disclosure is a violation of the written description requirement of 35 U.S.C. 112(a)  or pre-AIA  35 U.S.C. 112, first paragraph. See, e.g., 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); In re Ruschig, 379 F.2d 990, 995, 154 USPQ 118, 123 (CCPA 1967) (If n-propylamine had been used in making the compound instead of n-butylamine, the compound of claim 13 would have resulted. Appellants submit to us, as they did to the board, an imaginary specific example patterned on specific example 6 by which the above butyl compound is made so that we can see what a simple change would have resulted in a specific supporting disclosure being present in the present specification. The trouble is that there is no such disclosure, easy though it is to imagine it.) (emphasis in original); Rozbicki v. Chiang, 590 Fed.App’x 990, 996 (Fed. Cir. 2014) (non-precedential) (The court found that patentee, while attempting to obtain the broadest claim language possible during prosecution, cannot now improperly narrow its language by importing limitations not supported by the claim language or written description.). In Ex parte Ohshiro, 14 USPQ2d 1750 (Bd. Pat. App. & Inter. 1989), the Board affirmed the rejection under 35 U.S.C. 112, first paragraph, of claims to an internal combustion engine which recited at least one of said piston and said cylinder (head) having a recessed channel. The Board held that the application which disclosed a cylinder head with a recessed channel and a piston without a recessed channel did not specifically disclose the species of a channeled piston.
While these and other cases find that recitation of an undisclosed species may violate the description requirement, a change involving subgeneric terminology may or may not be acceptable. Applicant was not entitled to the benefit of a parent filing date when the claim was directed to a subgenus (a specified range of molecular weight ratios) where the parent application contained a generic disclosure and a specific example that fell within the recited range because the court held that subgenus range was not described in the parent application. In re Lukach, 442 F.2d 967, 169 USPQ 795 (CCPA 1971). On the other hand, in Ex parte Sorenson, 3 USPQ2d 1462 (Bd. Pat. App. & Inter. 1987), the subgeneric language of aliphatic carboxylic acid and aryl carboxylic acid did not violate the written description requirement because species falling within each subgenus were disclosed as well as the generic carboxylic acid. See also In re Smith, 458 F.2d 1389, 1395, 173 USPQ 679, 683 (CCPA 1972) (Whatever may be the viability of an inductive-deductive approach to arriving at a claimed subgenus, it cannot be said that such a subgenus is necessarily described by a genus encompassing it and a species upon which it reads. (emphasis added)). Each case must be decided on its own facts in terms of what is reasonably communicated to those skilled in the art. In re Wilder, 736 F.2d 1516, 1520, 222 USPQ 369, 372 (Fed. Cir. 1984).
Claim 6 and dependent claims thereof are drawn to “a unit dose vial comprising…4mL,…of a fully human anti-interferon gamma (IFNγ) monoclonal….”
At various paragraphs the instant specification teaches unit dose vials comprising 20 mL [0019], or 10-20 mL [0020], or 2-10 mL [0021], or “2, 5, 10 or 20 ml” [0164]; see also paragraphs 166-168.
However, nowhere does the instant specification teach or suggest “a unit dose vial comprising…4mL,…of a fully human anti-interferon gamma (IFNγ) monoclonal….”
Thus the claimed invention, which does not appear in the specification as filed, introduces a new concept and violates the description requirement of the first paragraph of 35 U.S.C. 112.
One way for applicant to overcome this rejection is by amending the claims so as to not contain new matter.  Alternatively, applicant is invited to point out in detail how the instant specification
provides sufficient written description support for the instant claims. See MPEP 714.02 and
2163.06.
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA  as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-10 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 11091543 (cited on an IDS) in view of Daugherty et al. (Advanced Drug Delivery Reviews 58 (2006) 686– 706) and Warne et al. (20060193850) (all cited herewith).
Instant claims 1 and 6 and are drawn to (emphasis added):
1. An injectable pharmaceutical formulation comprising: a) 25 mg/mL of a fully human anti-interferon gamma (IFNy) monoclonal antibody; and b) 1.55 mg/mL L-histidine, 3.14 mg/mL L-histidine monohydrochloride, monohydrate, 0.05 mg/mL Polysorbate 80, and 7.31 mg/mL sodium chloride (NaCl),wherein the pH is between 5.8 and 6.2, and wherein the antibody comprises a variable heavy chain complementarity determining region 1 (VH CDR1) comprising the amino acid sequence of SEQ ID NO: 1; a variable heavy chain complementarity determining region 2 (VH CDR2) comprising the amino acid sequence of SEQ ID NO: 2; a variable heavy chain complementarity determining region 3 (VH CDR3) comprising the amino acid sequence of SEQ ID NO: 3; a variable light chain complementarity determining region 1 (VL CDR1) comprising the amino acid sequence of SEQ ID NO: 4; a variable light chain complementarity determining region 2 (VL CDR2) region comprising the amino acid sequence of SEQ ID NO: 5; and a variable light chain complementarity determining region 3 (VL CDR3) region comprising the amino acid sequence of SEQ ID NO: 6.
6. A unit dose vial comprising, 2 mL, 4mL, 10 mL or 20 mL of a fully human anti- interferon gamma (IFNy) monoclonal antibody solution suitable for injection,wherein the solution comprises 1.55 mg/mL L-histidine, 3.14 mg/mL L-histidine monohydrochloride, monohydrate, 0.05 mg/mL Polysorbate 80, and 7.31 mg/mL sodium chloride (NaCl), wherein the pH of the solution is between 5.8 and 6.2, wherein the concentration of antibody is at 25 mg/mL, and wherein the antibody comprises: a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 1; a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 2; a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 3; a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 4; a VL CDR2 region comprising the amino acid sequence of SEQ ID NO: 5; and a VL CDR3 region comprising the amino acid sequence of SEQ ID NO: 6.
Reference claims 1-9 are drawn to (emphasis added):
1. An injectable pharmaceutical formulation comprising: a) 5 mg/mL of a fully human anti-interferon gamma (IFNγ) monoclonal antibody; and b) 1.55 mg/mL L-histidine, 3.14 mg/mL L-histidine monohydrochloride, monohydrate, 0.05 mg/mL Polysorbate 80, and 7.31 mg/mL sodium chloride (NaCl), wherein the pH is between 5.8 and 6.2, and wherein the antibody comprises a variable heavy chain complementarity determining region 1 (VH CDR1) comprising the amino acid sequence of SYAMS (SEQ ID NO: 1); a variable heavy chain complementarity determining region 2 (VH CDR2) comprising the amino acid sequence of AISGSGGSTYYADSVKG (SEQ ID NO: 2); and a variable heavy chain complementarity determining region 3 (VH CDR3) comprising the amino acid sequence of DGSSGWYVPHWFDP (SEQ ID NO: 3); a variable light chain complementarity determining region 1 (VL CDR1) comprising the amino acid sequence of TRSSGSIASNYVQ (SEQ ID NO: 4); a variable light chain complementarity determining region 2 (VL CDR2) region comprising the amino acid sequence of EDNQRPS (SEQ ID NO: 5); and a variable light chain complementarity determining region 3 (VL CDR3) region comprising the amino acid sequence of QSYDGSNRWM (SEQ ID NO: 6).
2. The formulation of claim 1, wherein the antibody comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 47, and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 48.
3. A method of treating a condition in a human subject by administering the formulation of claim 1, wherein the condition is primary hemophagocytic lymphohistiocytosis (HLH) or secondary HLH.
4. The method of claim 3, wherein the human subject is pediatric or adult.
5. A unit dose vial comprising, 2 ml or 10 ml of a fully human anti-interferon gamma (IFNγ) monoclonal antibody solution suitable for injection, wherein the solution comprises 1.55 mg/mL L-histidine, 3.14 mg/mL L-histidine monohydrochloride, monohydrate, 0.05 mg/mL Polysorbate 80, and 7.31 mg/mL sodium chloride (NaCl), wherein the antibody comprises a variable heavy chain complementarity determining region 1 (VH CDR1) comprising the amino acid sequence of SYAMS (SEQ ID NO: 1); a variable heavy chain complementarity determining region 2 (VH CDR2) comprising the amino acid sequence of AISGSGGSTYYADSVKG (SEQ ID NO: 2); and a variable heavy chain complementarity determining region 3 (VH CDR3) comprising the amino acid sequence of DGSSGWYVPHWFDP (SEQ ID NO: 3); a variable light chain complementarity determining region 1 (VL CDR1) comprising the amino acid sequence of TRSSGSIASNYVQ (SEQ ID NO: 4); a variable light chain complementarity determining region 2 (VL CDR2) region comprising the amino acid sequence of EDNQRPS (SEQ ID NO: 5); and a variable light chain complementarity determining region 3 (VL CDR3) region comprising the amino acid sequence of QSYDGSNRWM (SEQ ID NO: 6), wherein the concentration of antibody is at 5 mg/ml, and wherein the pH of the solution is between 5.8 and 6.2.
6. The unit dose vial of claim 5, wherein the antibody is solubilized in the solution such that the solution is clear, colorless, and without precipitate.
7. The unit dose vial of claim 5, wherein the antibody comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO. 47, and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 48.
8. A method of treating a condition in a human subject by administering the unit dose vial of claim 5, wherein the condition is primary hemophagocytic lymphohistiocytosis (HLH) or secondary HLH.
9. The method of claim 8, wherein the human subject is pediatric or adult.
However, the reference claims are not drawn to formulations or unit doses comprising 25 mg/mL of the anti-IFN-γ antibody, or methods of treatment comprising administering said formulations or unit doses comprising 25 mg/mL of the anti-IFN-γ antibody.
Table 1 of Daugherty teaches various antibodies formulated at or around 25 mg/mL.
At page 688, 1st full paragraph, Daugherty teaches “…the ability to prepare large quantities of an
antibody that could be administered for chronic therapy resulted in a plethora of new and novel
applications… New issues, related to identifying stable formulations such as high concentration formulations that might reduce the volume of antibody administrations, arose in the move from intravenous infusions to the realm of subcutaneous injection strategies.”
Notably, in the paragraphs bridging pages 687-88, Daugherty describes how one advantage of a higher concentration antibody formulation is that it reduces the need for a carrier protein.
At the same time, Daugherty notes that antibody formulations having concentrations > 50 mg/mL or at 100 mg/mL due to higher viscosity and presumably aggregation (see page 690, lines 3-6 and page 692, right col., 1st full paragraph).
In this regard, section 4.3 of Daugherty entitled “Aggregation” teaches the following in the first paragraph (emphasis added):
“Liquid formulations of protein therapeutics frequently exhibit a decrease in concentration due to adsorptivity to container walls at low concentration and can show aggregation events at high concentrations.  Initial preparations of antibody drugs were administered in acute situations by IV infusion that could allow for medium protein concentration (1–10 mg/ml) formulations not dramatically affected by adherence or aggregation losses.  As antibody-based drugs became more widely used in chronic care, high concentration formulations that would allow for clinically acceptable SC injection volumes became desirable and aggregation became an important concern for designing formulations.  Along with aggregation events, protein solutions at concentrations >50 mg/ml may become sufficiently viscous as to no longer readily pass through the gauge of a needle that would be comfortable for patients’ use.  Some antibodies demonstrate high concentration viscosity issues while others do not.  For example, the anti-respiratory syncytial viral antibody Synagis© is formulated at 100 mg/ml protein and is administered successfully by IM injection.  Thus, addressing viscosity, adsorptive loss and aggregation in any specific antibody formulation will likely be performed on a case-by-case basis.”
At same time on page 693, right col., 1st full paragraph Daugherty teaches (emphasis added):
“Protection from aggregation can be limited in antibody formulations by the addition of surface-active agents such as detergents, both charged and uncharged.  As an interesting aside, such surface-active agents can help reduce protein loss due to adherence to surfaces that can occur with low concentration protein formulations.  Polysorbate 20 and 80 (now available from a vegetal source) are examples of detergents that are widely used to reduce the rate of protein aggregation in high concentration antibody drug formulations.”
From the teachings of Daugherty set forth above it would have been obvious to the ordinarily skilled artisan that:
(i) higher concentration antibody formulations are advantageous in allowing for non-intravenous administration, while simulataneously lessening the need for the added presence of a carrier protein;
(ii) formulations > 50 mg/mL present viscosity and aggregation concerns;
(iii) thus, the formulation of an antibody at ever higher concentration, while minimizing aggregation and prohibitive viscosity is an empiric process of routine optimization to be performed on a case-by-case basis for any given antibody.
The teachings of Warne are exemplary of this empiric process of routine optimization applied to a given antibody (anti-Aβ), formulated with a buffering component that maintains a physiologically suitable pH, such as histidine, and stabilizers that minimize aggregation, such as polysorbate 80.
For example, at paragraphs 0151 Warne teaches the formulation of an anti-Aβ at a wide range of concentrations including 25 mg/mL.  Likewise, at paragraph 0167, Warne teaches the formulation of an anti-Aβ at a wide range of concentrations including, e.g., from about 17 mg/mL to about 23 mg/mL, or about 10 mg/mL to about 30 mg/mL.  Similar teachings regarding formulation of an anti-Aβ at about 20 to about 23 mg/mL are found in paragraphs 0021, 0023, 0025.
Note that at paragraph 0018 Warne teaches their antibody formulations are suitable for subcutaneous administration and at paragraph 0035 Warne teaches an antibody formulations comprising histidine as a buffering agent and polysorbate 80 as a stabilizer which can be administered subcutaneously.
(emphasis added):
“The present invention provides formulations designed to provide stability and to maintain the biological activity of an incorporated biologically active protein, in particular Aβ binding proteins or polypeptides, such as, for example, Aβ antibodies or fragments or portions thereof.  The invention further provides polypeptide formulations, such as, for example, stabilized liquid polypeptide formulations that are resistant to the formation of undesired polypeptide by-products.
The integrity of antigen-binding polypeptides for therapeutic use is especially important because if the polypeptide forms by-products, for example, aggregates or degradation fragments during storage, bioactivity may be lost, thereby jeopardizing the therapeutic activity of the molecule per unit dose. In addition, there is an acute desire to stabilize therapeutic polypeptides intended for specialized functions, for delivery and use in certain biological indications, for example, treating neurodegenerative conditions, where a polypeptide must traverse the blood-brain-barrier (BBB) and bind a target antigen.
In one aspect, the present invention provides a stabilized formulation including at least one Aβ binding polypeptide, at least one tonicity agent, wherein the tonicity agent is present in an amount sufficient to render the formulation suitable for administration, and at least one
buffering agent in an amount sufficient to maintain a physiologically suitable pH. The formulation can be a lyophilized or a liquid formulation. Some formulations include at least
one antioxidant, such as, for example, an amino acid antioxidant, such as, for example, methionine. In some formulations, the tonicity agent is mannitol or NaCl.  In some
formulations, at least one buffering agent is succinate, sodium phosphate, or an amino acid such as histidine.  Preferred formulations also include at least one stabilizer such as, for example, polysorbate 80.  In some formulations, the stabilizer is polysorbate 80, the antioxidant is methionine, the tonicity agent is mannitol, sorbitol or NaCl, and the buffering agent is histidine….”
Note that at paragraph 0018 Warne teaches their antibody formulations are suitable for subcutaneous administration and at paragraph 0035 Warne teaches an antibody formulations comprising histidine as a buffering agent and polysorbate 80 as a stabilizer which can be administered subcutaneously.
Given the reference claims and the teachings of Daugherty et al. and Warne et al., it would have been obvious to the ordinarily skilled artisan, and the ordinarily skilled artisan would have been motivated to make a pharmaceutical formulation comprising
Insofar as neither Daugherty nor Warne explicitly teach, e.g., an injectable pharmaceutical formulation comprising: a) 25 mg/mL of a fully human anti-interferon gamma (IFNγ) monoclonal antibody; and b) 1.55 mg/mL L-histidine, 3.14 mg/mL L-histidine monohydrochloride, monohydrate, 0.05 mg/mL Polysorbate 80, and 7.31 mg/mL sodium chloride (NaCl),wherein the pH is between 5.8 and 6.2, and wherein the antibody comprises a variable heavy chain complementarity determining region 1 (VH CDR1) comprising the amino acid sequence of SEQ ID NO: 1; a variable heavy chain complementarity determining region 2 (VH CDR2) comprising the amino acid sequence of SEQ ID NO: 2; a variable heavy chain complementarity determining region 3 (VH CDR3) comprising the amino acid sequence of SEQ ID NO: 3; a variable light chain complementarity determining region 1 (VL CDR1) comprising the amino acid sequence of SEQ ID NO: 4; a variable light chain complementarity determining region 2 (VL CDR2) region comprising the amino acid sequence of SEQ ID NO: 5; and a variable light chain complementarity determining region 3 (VL CDR3) region comprising the amino acid sequence of SEQ ID NO: 6, and/or to reduce the need for a carrier protein (claim 1), or a unit dose vial comprising, 2 mL, 4mL, 10 mL or 20 mL of a fully human anti- interferon gamma (IFNγ) monoclonal antibody solution suitable for injection, wherein the solution comprises 1.55 mg/mL L-histidine, 3.14 mg/mL L-histidine monohydrochloride, monohydrate, 0.05 mg/mL Polysorbate 80, and 7.31 mg/mL sodium chloride (NaCl), wherein the pH of the solution is between 5.8 and 6.2, wherein the concentration of antibody is at 25 mg/mL, and wherein the antibody comprises: a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 1; a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 2; a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 3; a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 4; a VL CDR2 region comprising the amino acid sequence of SEQ ID NO: 5; and a VL CDR3 region comprising the amino acid sequence of SEQ ID NO: 6 (claim 6),
or dependent claims thereof, the reference claims are drawn to pharmaceutical formulations and unit dose vials comprising 5 mg/mL of the claimed antibody, and to methods of treatment making use of said pharmaceutical formulations and unit dose vials.
It is submitted that,
(i) since one of ordinary skill in the art would have been motivated to determine the optimum or workable variables for any antibody formulation; and
(ii) given the teachings of Daugherty and Warne set forth above;
(iii) the ordinarily skilled artisan would have been motivated to, and would have had a reasonable expectation of, successfully producing not only the formulation / unit dose vial of the reference claims (having the antibody at 5 mg/mL), but also of successfully producing a formulation comprising a relatively high concentration of therapeutic, i.e., > 5 mg/mL to < 50 mg/mL, for the purpose of facilitating convenient subcutaneous dosing and/or minimizing, if not eliminating, the need for a carrier protein.
Insofar as neither Daugherty nor Warne explicitly direct the ordinarily skilled artisan to make a 25 mg/kg formulation / unit dose vial comprising the particular antibody of the instant claims, applicant’s attention is drawn to MPEP 2144.05(II)(A), Routine Optimization - Optimization Within Prior Art Conditions or Through Routine Experimentation:
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree “will not sustain a patent”); In re Williams, 36 F.2d 436, 438 (CCPA 1929) (“It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.”). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) (identifying “the need for caution in granting a patent based on the combination of elements found in the prior art.”).
Although this passage does not specifically teach, for example, formulating any particular antibody, e.g., the anti-IFNγ antibody of the instant claims, at any particular concentration, e.g., at 25 mg/kg, in the presence of certain buffering and stabilizing / solubilizing components, this passage nonetheless points to numerous variables that affect the function of inventions, such as concentration of reagents and temperature ranges.  Furthermore, this passage indicates that optimization of such variables is often an obvious activity for the ordinarily skilled artisan.
Additionally, as set forth in MPEP 2144.05(II)(B), there is a Motivation to Optimize Result-Effective Variables:
…  In In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977), the CCPA held that a particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation, because obvious to try is not a valid rationale for an obviousness finding. However, in KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court held that obvious to try was a valid rationale for an obviousness finding, for example, when there is a design need or market demand and there are a finite number of solutions. 550 U.S. at 421 (The same constricted analysis led the Court of Appeals to conclude, in error, that a patent claim cannot be proved obvious merely by showing that the combination of elements was ‘[o]bvious to try.’ ... When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under §103.). Thus, after KSR, the presence of a known result-effective variable would be one, but not the only, motivation for a person of ordinary skill in the art to experiment to reach another workable product or process.
Thus, given the invention of the reference claims, and further given the teachings of Daugherty and Warne set forth above, it was prima facie obvious to formulate the anti-IFNγ antibody of the instant claims at a variety relatively high concentrations that are > 5 mg/mL and < 50 mg/mL, including, e.g., 25 mg/mL, for the purpose of facilitating convenient subcutaneous dosing and/or minimizing, if not eliminating, the need for a carrier protein.
In view of the reference teachings it was apparent that one of ordinary skill in the art would have had a reasonable expectation of success in arriving at the claimed invention.  Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made.
No claims are allowed.


NEXT OFFICE 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 .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection.  Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.  Applicant's submission filed on 4-25-24 has been entered.
Reasons for Allowance
The following is an examiner’s statement of reasons for allowance:
Commonly, HLH patients are pediatric patients weighing less than 60 kg and are considered a “fragile” population due to the severity of their disease pathology (see, e.g., De Min et al. (2015),  ABSTRACT NUMBER: 3097, at 1st paragraph, and Jordan et al. (2015), Nl-0501: First Results from a Pilot Phase 2 Study in Children with Primary HLH, at pages 7-9, (both cited on an IDS).
Likewise, a form of HLH, known as macrophage activation syndrome (MAS) occurs in the context of systemic juvenile idiopathic arthritis (sJIA).
As described at page 295, left col., 1st paragraph of Ravelli et al. (2012), cited on an IDS, like the “fragile” patient population described by De Min, pediatric patients suffering from MAS in the context of sJIA are similarly at risk of death and urgently in need of rapid treatment, typically in a clinical / hospital setting:
“MAS is becoming an increasingly recognized, sometimes fatal, complication of sJIA disease flare.  Because of the urgency in making the diagnosis of MAS and instituting appropriate therapy in a timely fashion, efforts are ongoing to establish timely, practical, and highly sensitive and specific criteria for recognizing MAS in children with sJIA.” (see also the “Main clinical, laboratory and pathological features of macrophage activation syndrome” reported in Table 1 of Ravelli).
Given the knowledge in the art described above it remains this examiner’s opinion that it would not have been obvious to the ordinarily skilled artisan that an anti-IFNγ antibody, such as the NI-0501 antibody of U.S. Patent Nos. 7700098 or  9682142 (both cited on an IDS), should be formulated at high dose, e.g., to facilitate sub-cutaneous self-administration in an at home setting (see Warne et al., European Journal of Pharmaceutics and Biopharmaceutics 78 (2011) 208–212, at page 208, left col., cited on an IDS) when the primary patient population to be treated is “fragile” and therefore most likely to be receiving treatment in a clinical setting rather than at home.
Any comments considered necessary by applicant must be submitted no later than the payment of the issue fee and, to avoid processing delays, should preferably accompany the issue fee.  Such submissions should be clearly labeled “Comments on Statement of Reasons for Allowance.”
Conclusion

CITED REFERENCE SUMMARIES: Ref US20060193850A1: Claims:
A stabilized formulation comprising at least one AÎ² binding polypeptide, at least one tonicity agent, wherein the tonicity agent is present in an amount sufficient to render the formulation suitable for administration, and at least one buffering agent in an amount sufficient to maintain a physiologically suitable pH.
The formulation of claim 1 , further comprising at least one antioxidant.
The formulation of claim 2 , wherein at least one antioxidant is methionine.
The formulation of claim 1 , wherein at least one tonicity agent is mannitol.
The formulation of claim 4 , wherein at least one tonicity agent is NaCl.
The formulation of claim 1 , wherein at least one buffering agent is histidine.
The formulation of claim 1 , wherein at least one buffering agent is succinate.
The formulation of claim 1 , wherein at least one buffering agent is sodium phosphate.
The formulation of claim 1 , further comprising at least one stabilizer.
The formulation of claim 9 , wherein at least one stabilizer is polysorbate 80.
The formulation of claim 1 , wherein at least one Aβ binding polypeptide is selected from the group consisting of an anti Aβ antibody, an anti Aβ antibody Fv fragment, an anti Aβ antibody Fab fragment, an anti Aβ antibody Fab′(2) fragment, an anti Aβ antibody Fd fragment, a single-chain anti Aβ antibody (scFv), a single domain anti Aβ antibody fragment (Dab), a beta-pleated sheet polypeptide comprising at least one antibody complementarity determining region (CDR) from an anti Aβ antibody, and a non-globular polypeptide comprising at least one antibody CDR from an anti Aβ antibody.
The formulation of claim 11 , wherein at least one AÎ² binding polypeptide is an anti AÎ² antibody.
The formulation of claim 12 , wherein the anti AÎ² antibody specifically binds to an epitope within residues selected from the group consisting of 1-7, 1-5, 3-7, 3-6, 13-28, 15-24, 16-24, 16-21, 19-22, 33-40, and 33-42 of AÎ².
The formulation of claim 13 , wherein the anti AÎ² antibody specifically binds to an epitope within residues 1-7.
The formulation of claim 13 , wherein the anti AÎ² antibody specifically binds to an epitope within residues 1-5.
The formulation of claim 13 , wherein the anti AÎ² antibody specifically binds to an epitope within residues 3-6.
The formulation of claim 13 , wherein the anti AÎ² antibody specifically binds to an epitope within residues 3-7.
The formulation of claim 13 , wherein the anti AÎ² antibody specifically binds to an epitope within residues 13-28.
The formulation of claim 13 , wherein the anti AÎ² antibody specifically binds to an epitope within residues 16-24.
The formulation of claim 13 , wherein the anti AÎ² antibody specifically binds to an epitope within residues 16-21.
The formulation of claim 13 , wherein the anti AÎ² antibody specifically binds to an epitope within residues 19-22.
The formulation of claim 12 , wherein the anti AÎ² antibody is selected from the group consisting of a humanized 3D6 antibody, a humanized 10D5 antibody, a humanized 12B4 antibody, a humanized 266 antibody, a humanized 12A11 antibody, and a humanized 15C11 antibody.
The formulation of claim 22 , further comprising a stabilizer and an antioxidant.
The formulation of claim 23 , wherein the stabilizer is polysorbate 80, the antioxidant is methionine, the tonicity agent is mannitol, sorbitol or NaCl, and the buffering agent is histidine.
The formulation of claim 22 , wherein the formulation is a lyophilized formulation.
The formulation of claim 22 , wherein the formulation is a liquid formulation.
The formulation of claim 22 , wherein the antibody is of isotype human IgG1.
The formulation of claim 22 , wherein the antibody is of isotype human IgG4.
The formulation of claim 12 , wherein the anti AÎ² antibody is present at a concentration of about 0.1 mg/ml to about 60 mg/ml.
The formulation of claim 12 , wherein the anti AÎ² antibody is present at a concentration of about 20 mg/ml.
The formulation of claim 12 , wherein the anti AÎ² antibody is present at a concentration of about 10 mg/ml.
The formulation of claim 23 , wherein at least one tonicity agent is D-mannitol at a concentration of about 1% w/v to about 10% w/v.
The formulation of claim 32 , wherein the concentration of D-mannitol is about 2% w/v to about 6% w/v.
The formulation of claim 23 , wherein at least one buffering agent is histidine at a concentration of about 0.1 mM to about 25 mM.
The formulation of claim 23 , wherein the formulation has a pH of about 5.5 to about 6.5.
The formulation of claim 22 , wherein the anti AÎ² antibody is a humanized 3D6 antibody.
The formulation of claim 22 , wherein the anti AÎ² antibody is a humanized 12A11 antibody.
The formulation of claim 22 , wherein the anti AÎ² antibody is a humanized 266 antibody.
The formulation of claim 22 , wherein the anti AÎ² antibody is a humanized 15C11 antibody.
A formulation stable for at least about 12 months at a temperature of above freezing to about 10° C. and having a pH of about 5.5 to about 6.5, comprising: i. at least one Aβ antibody at a concentration of about 1 mg/ml to about 30 mg/ml; ii. mannitol at a concentration of about 4% w/v or NaCl at a concentration of about 150 mM; iii. about 5 mM to about 10 mM histidine or succinate; and iv. 10 mM methionine.
i. at least one AÎ² antibody at a concentration of about 1 mg/ml to about 30 mg/ml;
ii. mannitol at a concentration of about 4% w/v or NaCl at a concentration of about 150 mM;
iii. about 5 mM to about 10 mM histidine or succinate; and
iv. 10 mM methionine.
The formulation of claim 40 , wherein the formulation is stable for at least about 24 months at a temperature of about 2° C. to 8° C., and comprises polysorbate 80 at a concentration of about 0.001% w/v to about 0.01% w/v.
The formulation of claim 40 , wherein the formulation has a pH of about 6.0 to about 6.5 and comprises about 10 mg/ml AÎ² antibody, about 10 mM histidine and about 4% w/v mannitol and about 0.005% w/v polysorbate 80.
The formulation of claim 40 , wherein the formulation has a pH of about 6.0 to about 6.2 and comprises about 20 mg/ml AÎ² antibody, about 10 mM histidine, about 4% w/v mannitol and about 0.005% w/v polysorbate 80.
The formulation of claim 40 , wherein the formulation has a pH of about 6.0 to about 6.2 and comprises about 30 mg/ml AÎ² antibody, about 10 mM histidine, about 4% w/v mannitol and about 0.005% w/v polysorbate 80.
The formulation of claim 40 , wherein the AÎ² antibody is selected from the group consisting of a humanized 3D6 antibody, a humanized 10D5 antibody, a humanized 12B4 antibody, a humanized 266 antibody, a humanized 12A11 antibody, and a humanized 15C11 antibody.
The formulation of claim 40 , wherein the formulation has a pH of about 6.0 to 6.5 and comprises about 10 mM histidine, about 4% w/v mannitol and about 2 mg/ml to about 20 mg/ml of an AÎ² antibody selected from the group consisting of a humanized 3D6 antibody, a humanized 10D5 antibody, a humanized 12B4 antibody, and a humanized 12A11 antibody.
The formulation of claim 40 , wherein the formulation has a pH of about 6.0 to 6.5 and comprises about 10 mM histidine, about 150 mM NaCl and about 2 mg/ml to about 20 mg/ml of an AÎ² antibody selected from the group consisting of a humanized 12B4 antibody, and a humanized 12A11 antibody.
The formulation of claim 40 , wherein the formulation has a pH of about 6.0 to 6.5 and comprises about 10 mM histidine, about 4% w/v mannitol and about 2 mg/ml to about 20 mg/ml of an AÎ² antibody selected from the group consisting of a humanized 266 antibody and a humanized 15C11 antibody.
A formulation stable for at least about 24 months at a temperature of about 2° C. to about 8° C. and having a pH of about 5.5 to about 6.5, comprising about 2 mg/ml to about 23 mg/ml of a humanized 3D6 antibody, about 10 mM histidine and about 10 mM methionine.
The formulation of claim 49 , further comprising about 4% w/v mannitol.
The formulation of claim 49 , further comprising polysorbate 80 at a concentration of about 0.001% w/v to about 0.01% w/v.
The formulation of claim 51 , comprising about 0.005% w/v polysorbate 80.
The formulation of claim 49 , wherein the humanized 3D6 antibody is present at a concentration of about 17 mg/ml to about 23 mg/ml.
A formulation stable for at least about 24 months at a temperature of about 2° C. to about 8° C. and having a pH of about 5.5 to about 6.5, comprising about 2 mg/ml to about 23 mg/ml of a humanized 3D6 antibody, about 10 mM succinate, about 10 mM methionine, about 4% w/v mannitol and about 0.005% w/v polysorbate 80.
A formulation stable for at least about 24 months at a temperature of about 2° C. to about 8° C. and having a pH of about 6.0 to about 6.5, comprising about 2 mg/ml to about 30 mg/ml of a humanized 266 antibody, about 10 mM histidine and about 10 mM methionine.
The formulation of claim 55 , further comprising about 4% w/v mannitol.
The formulation of claim 55 , further comprising polysorbate 80 at a concentration of about 0.001% w/v to about 0.01% w/v.
A formulation stable for at least about 24 months at a temperature of about 2° C. to about 8° C. and having a pH of about 6.0 to about 6.5, comprising about 2 mg/ml to about 30 mg/ml of a humanized 12A11 antibody, about 10 mM histidine and about 10 mM methionine.
The formulation of claim 58 , further comprising about 150 mM NaCl.
The formulation of claim 58 , further comprising polysorbate 80 at a concentration of about 0.001% w/v to about 0.01% w/v.
A formulation stable for at least about 24 months at a temperature of about 2° C. to about 8° C. and having a pH of about 6.0 to about 6.5, comprising about 2 mg/ml to about 20 mg/ml of a humanized 12A11 antibody, about 5 mM histidine, about 10 mM methionine, about 4% w/v mannitol and about 0.005% w/v polysorbate 80.
A formulation stable when thawed from about −50° c. to about −80° c., comprising about 40 to about 60 mg/ml of an anti Aβ antibody, about 1.0 mg/ml to about 2.0 mg/ml histidine, about 1.0 mg/ml to 2.0 mg/ml methionine and about 0.05 mg/ml polysorbate 80, wherein the formulation has a pH of about 6.0.
The formulation of claim 62 , wherein mannitol is excluded.
The formulation of claim 63 , wherein the AÎ² antibody is a humanized 3D6 antibody.
The formulation of claim 63 , wherein the AÎ² antibody is a humanized 266 antibody.
A formulation comprising about 20 mg/mL anti AÎ² antibody, about 10 mM L-histidine, about 10 mM methionine, about 4% mannitol and having a pH of about 6.
A formulation comprising about 30 mg/mL anti AÎ² antibody, about 10 mM succinate, about 10 mM methionine, about 6% mannitol and having a pH of about 6.2.
A formulation comprising about 20 mg/mL anti AÎ² antibody, about 10 mM L-histidine, about 10 mM methionine, about 4% mannitol, about 0.005% polysorbate 80, and having a pH of about 6.
A formulation comprising about 10 mg/mL anti AÎ² antibody, about 10 mM succinate, about 10 mM methionine, about 10% mannitol, about 0.005% polysorbate 80, and having a pH of about 6.5.
A formulation comprising about 5 mg/mL to about 20 mg/mL anti AÎ² antibody, about 5 mM to about 10 mM L-histidine, about 10 mM methionine, about 4% mannitol, about 0.005% polysorbate 80, and having a pH of about 6.0 to about 6.5.
A formulation comprising about 5 mg/mL to about 20 mg/mL anti AÎ² antibody, about 5 mM to about 10 mM L-histidine, about 10 mM methionine, about 150 mM NaCl, about 0.005% polysorbate 80, and having a pH of about 6.0 to about 6.5.
A pharmaceutical unit dosage form, comprising a formulation comprising: a. about 10 mg to about 250 mg of an anti AÎ² antibody; b. about 4% mannitol or about 150 mM NaCl; c. about 5 mM to about 10 mM histidine or succinate; and d. about 10 mM methionine
a. about 10 mg to about 250 mg of an anti AÎ² antibody;
b. about 4% mannitol or about 150 mM NaCl;
c. about 5 mM to about 10 mM histidine or succinate; and
d. about 10 mM methionine
The pharmaceutical unit dosage form of claim 72 , comprising about 0.001% to about 0.1% polysorbate 80.
The pharmaceutical unit dosage form of claim 73 , comprising about 40 mg to about 60 mg of the anti AÎ² antibody.
The pharmaceutical unit dosage form of claim 73 , comprising about 60 mg to about 80 mg of the anti AÎ² antibody.
The pharmaceutical unit dosage form of claim 73 , comprising about 80 mg to about 120 mg of the anti AÎ² antibody.
The pharmaceutical unit dosage form of claim 73 , comprising about 120 mg to about 160 mg of the anti AÎ² antibody.
The pharmaceutical unit dosage form of claim 73 , comprising about 160 mg to about 240 mg of the anti AÎ² antibody
A therapeutic product, comprising: a. a glass vial, comprising a formulation comprising: i. about 10 mg to about 250 mg of a humanized anti AÎ² antibody, ii. about 4% mannitol or about 150 mM NaCl, iii. about 5 mM to about 10 mM histidine, and iv. about 10 mM methionine; and b. labeling for use comprising instructions to use the appropriate volume necessary to achieve a dose of about 0.15 mg/kg to about 5 mg/kg.
a. a glass vial, comprising a formulation comprising: i. about 10 mg to about 250 mg of a humanized anti AÎ² antibody, ii. about 4% mannitol or about 150 mM NaCl, iii. about 5 mM to about 10 mM histidine, and iv. about 10 mM methionine; and
i. about 10 mg to about 250 mg of a humanized anti AÎ² antibody,
ii. about 4% mannitol or about 150 mM NaCl,
iii. about 5 mM to about 10 mM histidine, and
iv. about 10 mM methionine; and
b. labeling for use comprising instructions to use the appropriate volume necessary to achieve a dose of about 0.15 mg/kg to about 5 mg/kg.
The therapeutic product of claim 79 , wherein the dose is about 0.5 mg/kg to about 3 mg/kg.
The therapeutic product of claim 79 , wherein the dose is about 1 mg/kg to about 2 mg/kg.
The therapeutic product of claim 79 , wherein the anti AÎ² antibody concentration is about 10 mg/ml to about 60 mg/ml.
The therapeutic product of claim 79 , wherein the anti AÎ² antibody concentration is about 20 mg/ml.
The therapeutic product of claim 79 , further comprising about 0.005% polysorbate 80.
The therapeutic product of claim 79 , wherein the use is a subcutaneous administration.
The therapeutic product of claim 79 , wherein the use is an intravenous administration.
Ref US11091543: Claims:
1. An injectable pharmaceutical formulation comprising:
a) 5 mg/mL of a fully human anti-interferon gamma (IFNγ) monoclonal antibody; and
b) 1.55 mg/mL L-histidine, 3.14 mg/mL L-histidine monohydrochloride, monohydrate, 0.05 mg/mL Polysorbate 80, and 7.31 mg/mL sodium chloride (NaCl),
wherein the pH is between 5.8 and 6.2, and
wherein the antibody comprises a variable heavy chain complementarity determining region 1 (VH CDR1) comprising the amino acid sequence of SYAMS (SEQ ID NO: 1); a variable heavy chain complementarity determining region 2 (VH CDR2) comprising the amino acid sequence of AISGSGGSTYYADSVKG (SEQ ID NO: 2); and a variable heavy chain complementarity determining region 3 (VH CDR3) comprising the amino acid sequence of DGSSGWYVPHWFDP (SEQ ID NO: 3); a variable light chain complementarity determining region 1 (VL CDR1) comprising the amino acid sequence of TRSSGSIASNYVQ (SEQ ID NO: 4); a variable light chain complementarity determining region 2 (VL CDR2) region comprising the amino acid sequence of EDNQRPS (SEQ ID NO: 5); and a variable light chain complementarity determining region 3 (VL CDR3) region comprising the amino acid sequence of QSYDGSNRWM (SEQ ID NO: 6).
2. The formulation of claim 1, wherein the antibody comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 47, and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 48.
3. A method of treating a condition in a human subject by administering the formulation of claim 1, wherein the condition is primary hemophagocytic lymphohistiocytosis (HLH) or secondary HLH.
4. The method of claim 3, wherein the human subject is pediatric or adult.
5. A unit dose vial comprising, 2 ml or 10 ml of a fully human anti-interferon gamma (IFNγ) monoclonal antibody solution suitable for injection,
wherein the solution comprises 1.55 mg/mL L-histidine, 3.14 mg/mL L-histidine monohydrochloride, monohydrate, 0.05 mg/mL Polysorbate 80, and 7.31 mg/mL sodium chloride (NaCl),
wherein the antibody comprises a variable heavy chain complementarity determining region 1 (VH CDR1) comprising the amino acid sequence of SYAMS (SEQ ID NO: 1); a variable heavy chain complementarity determining region 2 (VH CDR2) comprising the amino acid sequence of AISGSGGSTYYADSVKG (SEQ ID NO: 2); and a variable heavy chain complementarity determining region 3 (VH CDR3) comprising the amino acid sequence of DGSSGWYVPHWFDP (SEQ ID NO: 3); a variable light chain complementarity determining region 1 (VL CDR1) comprising the amino acid sequence of TRSSGSIASNYVQ (SEQ ID NO: 4); a variable light chain complementarity determining region 2 (VL CDR2) region comprising the amino acid sequence of EDNQRPS (SEQ ID NO: 5); and a variable light chain complementarity determining region 3 (VL CDR3) region comprising the amino acid sequence of QSYDGSNRWM (SEQ ID NO: 6), wherein the concentration of antibody is at 5 mg/ml, and wherein the pH of the solution is between 5.8 and 6.2.
6. The unit dose vial of claim 5, wherein the antibody is solubilized in the solution such that the solution is clear, colorless, and without precipitate.
7. The unit dose vial of claim 5, wherein the antibody comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO. 47, and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 48.
8. A method of treating a condition in a human subject by administering the unit dose vial of claim 5, wherein the condition is primary hemophagocytic lymphohistiocytosis (HLH) or secondary HLH.
9. The method of claim 8, wherein the human subject is pediatric or adult.
Ref US20060193850: Claims:
A stabilized formulation comprising at least one Aβ binding polypeptide, at least one tonicity agent, wherein the tonicity agent is present in an amount sufficient to render the formulation suitable for administration, and at least one buffering agent in an amount sufficient to maintain a physiologically suitable pH. 2. The formulation of claim 1, further comprising at least one antioxidant. 3. The formulation of claim 2, wherein at least one antioxidant is methionine. 4. The formulation of claim 1, wherein at least one tonicity agent is mannitol. 5. The formulation of claim 4, wherein at least one tonicity agent is NaCl. 6. The formulation of claim 1, wherein at least one buffering agent is histidine. 7. The formulation of claim 1, wherein at least one buffering agent is succinate. 8. The formulation of claim 1, wherein at least one buffering agent is sodium phosphate. 9. The formulation of claim 1, further comprising at least one stabilizer. 10. The formulation of claim 9, wherein at least one stabilizer is polysorbate 80. 11. The formulation of claim 1, wherein at least one Aβ binding polypeptide is selected from the group consisting of an anti Aβ antibody, an anti Aβ antibody Fv fragment, an anti Aβ antibody Fab fragment, an anti Aβ antibody Fab′(2) fragment, an anti Aβ antibody Fd fragment, a single-chain anti Aβ antibody (scFv), a single domain anti Aβ antibody fragment (Dab), a beta-pleated sheet polypeptide comprising at least one antibody complementarity determining region (CDR) from an anti Aβ antibody, and a non-globular polypeptide comprising at least one antibody CDR from an anti Aβ antibody. 12. The formulation of claim 11, wherein at least one Aβ binding polypeptide is an anti Aβ antibody. 13. The formulation of claim 12, wherein the anti Aβ antibody specifically binds to an epitope within residues selected from the group consisting of 1-7, 1-5, 3-7, 3-6, 13-28, 15-24, 16-24, 16-21, 19-22, 33-40, and 33-42 of Aβ. 14. The formulation of claim 13, wherein the anti Aβ an
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