DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Applicant's preliminary amendment filed on 06/02/2023 is acknowledged.
Claims 1-13 and 15 are pending.
3. 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.
4. Claims 1-13 and 15 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
(i) Claims 1-12 and 15 are indefinite in the recitation of “stable” pharmaceutical formulation, because none of the nature (e.g. oxidation, aggregation, degradation), conditions (e.g. storage temperature), or degree (e.g. length of time) of the requisite “stability” are defined.
(ii) Claim 10 is indefinite because of an ambiguous combination of conjunctions is subclause (a), which recites ‘“no” sodium chloride “and”/or sodium sulphate.’
(iii) Claim 12 is indefinite in the recitation of “instructions” for “use” of the claimed article of manufacture, because the nature of the “use” in unknown.
(iv) Claim 15 is indefinite in the recitation of a method of treating “a disease” of the human or animal body, because the nature of the disease in unknown.
(v) Claim 13 is indefinite, because it encompasses the indefinite limitations of the claims on which it depends.
In view of the above, a person of ordinary skill in the art cannot unequivocally interpret the metes and bounds of the claims so as to understand how to avoid infringement. Applicant is reminded that any amendment must point to a basis in the specification so as not to add New Matter. See MPEP 714.02 and 2163.06.
5. The following is a quotation 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.
6. Claim 15 is rejected under 35 U.S.C. 112(a) as failing to comply with the enablement requirement. The claim contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The specification does not provide a sufficient enabling description of a method of treating a generically recited disease of the human or animal body comprising administering the recited composition comprising a generically recited IgG4 antibody of undefined specificity.
The specification does not enable one of skill in the art to make and use the invention as claimed (commensurate with the scope of the claims) without undue experimentation. Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized in In re Wands (858 F2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, limited working examples, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to make and use the claimed invention.
The claim encompasses in its breadth treatment of any disease whatsoever by administering an IgG4 antibody of any specificity. The antibody may not bind to a clinically relevant target, or to any known target.
The specification does not appear to provide guidance, direction, or working examples of treating any diseases by any antibodies.
A person of skill in the art would be aware of the inherent unpredictability in developing antibody-based therapeutics, as well as the risks and the resource-intensive nature of the required experimentation. Accordingly, the entire scope of experimentation required to develop treatment methods as claimed is left to those skilled in the art, the present claims and disclosure amounting to nothing more than an invitation to the skilled artisan to invent such methods.
7. The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
8. Claims 1-8 and 11-13 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Forrest et al. (US 20210380694).
Forrest teaches stable pharmaceutical formulations of pembrolizumab, an anti-PD-1 antibody of IgG4 isotype (e.g. [0127]).
In Example 2, Forrest exemplifies formulations comprising 5 mg/ml of pembrolizumab in 10 mM histidine buffer (pH 5.5), 1.4% sucrose, 10 mM antioxidant methionine, 1.4% 2-hydroxypropyl-beta-cyclodextrin (HPβC), and 0.004% or either polysorbate 20 or poloxamer ([0444]-[0445] and Table 4), thereby anticipating claims 1-6, 8 and 11.
Forrest further teaches and claims formulations comprising 5 to 250 mg/ml pembrolizumab in 5 mM to 20 mM histidine buffer containing 1.5% to 8.0% sorbitol, or 3% to 5% sorbitol, or 6% to 8% sucrose; a pharmaceutically acceptable salt of glycine, proline, or histidine; 1 mM to 20 mM L-methionine, 0.01% to 0.03% poloxamer or 0.01% to 0.10% polysorbate 80, and a metal chelator (e.g. claims 1, 3, 8, 9, 17 and 35), thereby anticipating claims 1-3, 5-8 and 11.
Forrest also teaches a container and a syringe containing the pharmaceutical formulation (e.g. [0031], [0340], [0356]), thereby anticipating claims 12 and 13.
9. Claims 1-5 and 9 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Banks et al. (US 20180289802).
Banks teaches and claims a pharmaceutical formulation comprising an anti-PD-1 antibody with a human IgG4 Fc region (e.g. claims 1 and 21), comprising 10 mM sodium acetate buffer (pH 5.2), 8.5% sucrose, and 0.005% polysorbate-80 (e.g. claim 92), i.e. the same constituents as recited in instant claim 9, subclause (e). Accordingly, Banks’ formulation is within the scope of instant claims 1-5 and 9, and as such anticipates these claims.
10. 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 of this title, 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
11. Claims 1 and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Banks et al. (US 20180289802) in view of any one of Gourbatsi et al. (2018), Toth et al. (2018), and Bhambhani et al. (2012).
Instant claim 10 recites seven formulations comprising specific concentrations of buffer, either sorbitol or sucrose, and polysorbate. For example, subclause (f) recites
acetate buffer at 10 mM and pH 5.5,
sucrose at 204.5 mM, which is equal to 7%, and
polysorbate 80 at 0.2 mg/ml, which is equal to 0.02%.
Banks teaches IgG4 antibody formulations comprising the same ingredients in very similar concentration, in particular (e.g. claim 69) formulations comprising:
an acetate, succinate, or histidine buffer at 10 nM and pH 4.7-5.7;
sucrose at 5-10%, in particular at 8.5%; and
polysorbate-20 or polysorbate-80 at 0.001-0.1%, in particular at 0.005%.
Instant claims are directed to a stable pharmaceutical formulation or a generic antibody of the IgG4 isotype. A person of skill in the art would be aware that stability of a monoclonal antibody in a liquid formulation depends not only on its isotype, but on the complete structure of the antibody molecule, including the amino acid sequences of the variable regions and on the specific nature of posttranslational modifications, such as glycosylation. Because of this, the composition of antibody formulation needs to be adjusted for each individual antibody to achieve acceptable stability. The strategies of such optimization were well-developed and routine in the art before the effective filing date of the claimed invention, including the availability of high-throughput platforms for this purpose, as described e.g. by Gourbatsi et al. (2018), Toth et al. (2018), and Bhambhani et al. (2012).
Therefore, given that optimization of concentrations of formulation ingredients to improve antibody stability was routine in the art before the effective filing date of the claimed invention, and that formulations exemplified by Banks comprise the same ingredients as instant claim 10 at very similar concentrations, a person of skill in the art would have arrived the present invention by using known techniques to improve similar products in the same way. See MPEP § 2141(III) and MPEP § 2143(I).
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
12. The following prior art references, cited of record but not presently relied upon, teach pharmaceutical formulations similar to those instantly claimed, and/or methods for optimizing such formulations:
Falconer R.J. Advances in liquid formulations of parenteral therapeutic proteins. Biotechnology Advances 37 (2019) 107412; 1-9.
Gervasi et al. Parenteral protein formulations: An overview of approved products within the European Union. European Journal of Pharmaceutics and Biopharmaceutics 131 (2018) 8–24.
Uchiyama S. Liquid formulation for antibody drugs. Biochimica et Biophysica Acta 1844 (2014) 2041–2052.
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13. Conclusion: no claim is allowed.
14. Any inquiry concerning this communication or earlier communications from the examiner should be directed to ILIA I OUSPENSKI whose telephone number is (571)272-2920. The examiner can normally be reached 8:30 AM – 5 PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Daniel Kolker can be reached at 571-272-3181. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ILIA I OUSPENSKI/ Primary Examiner, Art Unit 1644