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 .
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application is a 371 of PCT/KR2020/018247 filed December 14, 2020.
Acknowledgment is made of applicant's claim for foreign priority based on an application filed in Republic of Korea 10-2019-0167147 on December 13, 2019. The certified copy as required by 37 CFR 1.55 is filed on June 10, 2022 in the instant application. However, support for the claimed invention cannot be determined because the foreign priority documents provided are not in English. Therefore, the instant application is not entitled to the benefit of the foreign priority date of December 13, 2019. Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e). Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Accordingly, all claims have been given an effective filing date of December 14, 2020.
Election/Restriction
Applicant's election without traverse of Group I (Claims 1-17 and 20) and species election of:
Mixture of polyol and amino acid for a stabilizer
Trehalose for polyol
Arginine for amino acid
Polysorbate for a surfactant
in the reply filed on November 11, 2025 is acknowledged.
Upon further consideration, Examiner withdraws the restriction requirement between Group I (Claims 1-17 and 20) and Groups II-III (Claims 18-19) as set forth in the Office action mailed on 05/19/25. Claims 18-19 are hereby rejoined and fully examined for patentability. In view of the withdrawal of the restriction requirement, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application.
Claim Status
Claim listing filed on June 10, 2022 is pending. Claim 20 is new. Claims 1-20 are examined upon their merits.
Information Disclosure Statement
The information disclosure statements filed on 06/10/2022, 03/04/2024, 01/21/2025, and 06/11/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Specification
The disclosure is objected to because of the following informalities: The spacing of lines is inconsistent and appears to be 1 ½ in some lines and double spaced in other lines (see specifically paragraphs [0041]-[0042], [0046], [0072], [0079]-[0080], [0082], [0093], [0098]-[0099], and [0102]). 37 CFR 1.52(b)(2) states that the specification must have lines that are 1 1/2 or double spaced (emphasis added). Please select one line spacing and use it uniformly throughout the specification. Appropriate correction is required.
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.
Claims 1-18 and 20 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.
Claims 1-2, 5, 9-10, and 17 recite numerical ranges with the relative term “about.” Because there is no definition of the term “about” in the specification, the metes and bounds of Claims 1-18 and 20 cannot be readily determined (MPEP § 2173.05(b)III.A). For example, what are the bounds of “about 5 to about 200 mg/mL” in Claim 5? Is 250 mg/mL considered “about 200 mg/mL”? The scope of the claims are indefinite due to the relative term “about.”
Claim 13 recites wherein the surfactant is “sorbitan ester of another fatty acid.” It is understood in the art that sorbitan esters are produced by esterification of sorbitan with a variety of fatty acids such as lauric acid, palmitic acid, stearic acid, or oleic acid (as evidenced by Lanigan et al. International Journal of Toxicology 2002; page 94, paragraphs 2-4). However, it is unclear what is meant by “another fatty acid” in Claim 13 as no other fatty acid is recited. Possible claim language to overcome the indefiniteness is “sorbitan ester of a fatty acid.”
Claim 16 recites “wherein the pharmaceutical formulation is for administration by intravenous or subcutaneous injection.” As written, Claim 16 is directed to an intended use of the formulation (for administration), and it is unclear if the intended use confers some structural, material, or manipulative difference on the scope of the claim (see MPEP § 2111.02.II). Is the formulation of Claim 1 suitable for injection, or is a structural change required for the formulation to be suitable for injection? It is unclear how Claim 16 further limits the scope of the parent claim, rendering Claim 16 indefinite.
Note, “stabilizer” as recited in Claim 1 is defined by the specification using functional language as “a material added to prevent a state change or a chemical change when a sample material is left undisturbed or preserved” (paragraph [0020]). However, the functional language is not indefinite, because the term “stabilizer” was understood in the art prior to filing as evidenced by Cleland et al. Journal of Pharmaceutical Sciences 2001 (introduction paragraphs 2-3) and Bouyer et al. International Journal of Pharmaceutics 2012 (section 2.3).
Note, “treating” as recited in Claim 18 is not defined by the specification and is interpreted as alleviating the symptoms or complications of an established disease, delaying the progression of an established disease, and/or curing or eliminating an established disease.
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.
Claims 1-20 are rejected under 35 U.S.C. 103 as being unpatentable over Saluja et al. US 2022/0218607 (effectively filed April 2019) in view of Forrest US 2021/0380694 (filed November 2019) and Bahrenburg et al. Biotechnol. J. 2015 (of record in IDS).
In regard to Claims 1-2, 5-10, 12-13, 17, and 20, Saluja teaches antibody formulations with improved stability (paragraph [0001]). Specifically, Saluja teaches an antibody formulation comprising (i) an antibody or antigen-binding fragment thereof comprising any antibody known in the art; (ii) a salt comprising arginine glutamate; (iii) a stabilizer comprising any exemplary stabilizers described by Saluja or known in the art; (iv) a surfactant comprising any exemplary surfactant described by Saluja or known in the art; and (v) sterile water wherein the resulting aqueous antibody formulation is buffer-free (paragraph [0009]). In a specific embodiment, the antibody formulation comprises 0.1-200 mg/mL antibody, 0 mM buffer, 300-750 mM stabilizing salt, 2.0-6% sugars/polyols, and 0.02-0.06% surfactant and has a pH from about 5 to about 6.5 (paragraph [0133] and Table 1). Note, the % is in w/v (paragraph [0111]). Arginine glutamate is a pharmaceutically acceptable salt of arginine and can be used at about 300 mM (paragraphs [0148]-[0149]), trehalose can be used as the polyol stabilizer (paragraphs [0028] and [0056]), and polysorbate can be used as a non-ionic surfactant (paragraph [0110] and Table 2). The antibody formulations can further include an amino acid such as arginine (as opposed to the amino acid salt, arginine glutamate) at a final concentration of about 0.01 mM to about 750 mM (paragraph [0109]).
Note, MPEP § 2144.05 states: "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" (emphasis added). It would have been obvious to one of ordinary skill in the art prior to the effective filing date to determine all operable solute concentrations for the antibody formulation because concentrations are art-recognized result-effective variables which are routinely determined and optimized in the pharmaceutical arts. As stated in the MPEP quotation above, changes in proportions (such as concentrations) of a known concept are not inventive alterations.
In regard to Claim 11, the buffer that is not present in the formulation described above can comprise acetate, succinate, gluconate, histidine, citrate, or phosphate (paragraph [0016]).
In regard to Claims 14-15, Saluja teaches that the antibody formulations can further comprise an antioxidant wherein the antioxidant is methionine (paragraphs [0028]-[0029]).
In regard to Claim 16, Saluja teaches that the antibody formulations are suitable for intravenous or subcutaneous administration (paragraph [0027]).
In regard to Claim 18, Saluja teaches a method of treating a subject in need thereof that comprises administering to the subject a therapeutically effective amount of the aqueous antibody formulation (paragraphs [0124]-[0126]).
In regard to Claim 19, Saluja teaches a method of making an aqueous antibody formulation that includes mixing or combining solutes (i)-(iv) as described above in a sterile water solvent in amounts sufficient to generate any of the formulations described (paragraph [0009]).
While Saluja teaches that the formulation can comprise any antibody or antigen-binding fragment thereof known in the art, Saluja fails to teach wherein the antibody is an anti-PD-1 antibody (Claim 1), wherein the anti-PD-1 antibody is pembrolizumab comprising CDRs comprising SEQ ID NOs: 1-6 (Claims 3-4), or wherein the antibody formulation is administered to treat cancer (Claim 18).
Forrest teaches stable formulations of antibodies against PD-1 wherein the formulations comprise between 5-250 mg/mL anti-PD-1 antibody or antigen binding fragment thereof and the anti-PD-1 antibody is pembrolizumab (abstract). Forrest teaches that the CDR sequences of pembrolizumab comprise SEQ ID NOs: 1-3 and 6-8 (Table 2) which are 100% identical to instant SEQ ID NOs: 4-6 and 1-3, respectively. Forrest teaches a method of treating cancer by administering the anti-PD-1 antibody formulation (paragraphs [0396] and [0004]). The formulation can be administered intravenously or subcutaneously (paragraph [0357]).
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, at the time the invention was made, to substitute one known element for another to obtain predictable results. It would be obvious to substitute the known anti-PD-1 antibody taught by Forrest into the stable buffer-free antibody formulation taught by Saluja, because Saluja teaches that the stable formulation is applicable to any antibody known in the art. The motivation to formulate the anti-PD-1 cancer therapy in a buffer-free formulation is taught by Bahrenburg. Bahrenburg teaches that buffer-free antibody formulations offer toxicological benefits and avoid problems like protein destabilization and buffer-excipient-caused discoloration (title and introduction paragraph 3). Bahrenburg shows that buffer-free, highly concentrated liquid formulations of monoclonal antibodies can equal, and sometimes exceed, the performance of conventionally buffered formulations, suggesting that buffer-free protein formulations are a viable, and perhaps preferred, option for protein biotherapeutics (section 4.3). Bahrenburg further supports that the known anti-PD-1 antibody can be formulated in a known buffer-free solution with a reasonable expectation of success by teaching that solutions containing more than 50 mg/mL of antibody do not need any conventional buffering excipient to stabilize pH in a slightly acidic solution (introduction paragraph 2). Therefore, formulating the known anti-PD-1 antibody taught by Forrest in a known buffer-free antibody formulation taught by Saluja is obvious and would be preferable for the reasons taught by Bahrenburg.
Double Patenting
Note, no double patenting rejection is made in view of copending application 17/796,289, because the copending claims, while similar to the instant claims, require a stable anti-PD-1 antibody pharmaceutical formulation comprising a buffer wherein the instant claims require a buffer-free formulation.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SARAH COOPER PATTERSON whose telephone number is (703)756-1991. The examiner can normally be reached Monday - Friday 8:00am - 5:00pm EST.
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/SARAH COOPER PATTERSON/Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675
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