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 .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Priority
The instant application, filed 12/22/2023, is a 371 filing of PCT/EP22/67030, filed 06/22/2022, and claims foreign priority to EP22170678.1, filed 04/29/2022, EP21200882.5, filed 10/05/2021, and EP21181269.8, filed 06/23/2021.
Status of Claims/Application
Applicant’s preliminary amendment of 03/04/2024 is acknowledged. Claims 1-10 and 18 are amended; claims 13-17 are cancelled; and claims 19-25 are new. Claims 1-12 and 18-25 are currently pending and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 12/22/2023, 03/05/2024, 11/17/2025, and 05/11/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
Claim Interpretation
In the rejections of the instant office action, the limitation “one or more amino acids other than histidine”, as recited in instant claim 1, part (b), is interpreted to mean one or more amino acids that are not histidine. Additionally, under broadest reasonable interpretation, the claims are interpreted as encompassing formulations with histidine, as long as there are also one or more amino acids that are not histidine.
Claim Rejections - 35 USC § 102
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.
Claims 1-3, 5, 9, and 19-20 are rejected under 35 U.S.C. 102 (a)(1) and (a)(2) as being anticipated by CN 107325180 A (Caihui L., et al) 11 July 2017 English Translation from https://worldwide.espacenet.com/ on 2026-05-14 (original FOR reference cited on IDS of 12/22/2023).
CN’180 teaches anti-human PD-1 monoclonal antibody preparations suitable for subcutaneous injection. The stable liquid formulations can be effectively used in the preparation of drugs for the treatment of tumors, infectious diseases, autoimmune diseases, and anti-immune rejection (abstract).
CN’180 teaches a liquid formulation of an anti-human PD-1 monoclonal antibody comprising:
100 mg/mL of anti-human PD-1 monoclonal antibody;
10 mM phosphate buffer;
10 mM citrate buffer;
250 mM mannitol;
20 mM arginine; and
8 mg/mL of tween 20;
Where the pH of the preparation is 5.5 (pages 19-21, [0029]-[0036]; page 49, claim 9).
CN’180 also teaches that the formulation was tested with Keytruda (pembrolizumab, Merck) anti-human-PD-1 monoclonal antibody and achieved good stability (page 43, [0090]).
The formulation disclosed by CN’180 meets the instant claim limitations where the one or more amino acids other than histidine is arginine and the non-ionic surfactant is tween 20. It is noted that tween 20 is polysorbate 20 as evidenced by the instant disclosure, page 11, lines 31-32, which states “polysorbate 20 (i.e. Tween 20).”
Additionally, while the formulation of CN’180 comprises additional elements, such as mannitol and phosphate buffer, the formulation still anticipates the instant claims as the claims use “comprising” language with regards to the components of the formulation. The instant specification defines “comprising” as not excluding other elements (page 7, lines 9-10), which is consistent with the definition in MPEP 2111.03 I, which states that “The transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps.”
Thus, CN’180 anticipates instant claims 1-3, 5, 9, and 19-20.
Claims 1-6, 9, 10, and 19-23 are rejected under 35 U.S.C. 102 (a)(2) as being anticipated by US 2023/0054413 A1 (Jung, Y.S., et al) 23 Feb 2023; priority to 13 Dec 2019 (corresponds to WO 2021118321 A1 2021-06-17) both cited on IDS of 12/22/2023.
US’413 teaches pembrolizumab-containing pharmaceutical formulations (page 10, [0113]). US’413 further teaches that the formulations are liquid formulations suitable for subcutaneous or intravenous injection (page 4, [0032]).
US’413 teaches that the pharmaceutical formulations may comprise: (i) an anti-PD-1 antibody or an antigen binding fragment thereof; (ii) a stabilizer; and (iii) a buffer except histidine, and may have a pH of about 4.5 to about 6.5. The buffer except histidine may be succinate, citrate, acetate, phosphate or a combination thereof (page 6, [0049]). US’413 further teaches that the stabilizer can be an amino acid (page 3, [0024]-[0025]).
US’413 teaches formulation 8E in table 13, on page 11 as follows:
25 mg/mL pembrolizumab;
10 mM citrate buffer;
128 mM Arg-HCl; and
0.02% PS80;
With a pH of 5.5.
In the formulation disclosed by US’413, polysorbate 80 (PS80) is included at 0.02% which, based on the disclosure, is in w/v (page 4, [0029]). 0.02% w/v is equivalent to 0.2 mg/mL ((0.02 g/100mL) x (1000 mg/g) = (20 mg/ 100mL) = 0.2 mg/mL).
Thus, US’413 anticipates instant claims 1-6, 9, 10, and 19-23.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claims 1-10 and 18-24 are rejected under 35 U.S.C. 103 as being unpatentable over US 2023/0054413 A1 (Jung, Y.S., et al) 23 Feb 2023; priority to 13 Dec 2019 (corresponds to WO 2021118321 A1 2021-06-17) both cited on IDS of 12/22/2023.
The teachings of US’413 are as discussed in detail above.
US’413 further teaches that the amino acid, or stabilizer, in the formulation alternatively can be arginine, lysine, a pharmaceutically acceptable salt thereof, or a mixture thereof (page 3, [0024]). US’413 also teaches that the concentration of the amino acid as the stabilizer can be in the range of 0.1 to 300.0 mM, as well as 100.0 to 300.0 mM (page 3, [0024]).
US’413 further teaches a method for treating a cancer using the pharmaceutical compositions comprising administering a therapeutically effective amount of the pharmaceutical composition to a subject (page 6, [0050]). US’413 teaches that the cancer may include non-small cell lung cancer, urothelial cancer, colorectal cancer, small cell lung cancer, microsatellite instability high cancer, primary mediastinal large B-cell lymphoma, Merkel cell cancer, and cervical cancer (page 6, [0051]).
While US’413 does not exemplify a formulation comprising lysine or both lysine and arginine, or a method of treating cancer with the formulation, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to substitute the arginine in the formulation disclosed by US’413 with lysine or a combination of lysine with arginine and to use the formulations in methods of treating the cancers disclosed by US’413 based on the disclosure of US’413 as a whole. It would have been obvious to substitute the arginine with lysine or a combination of lysine and arginine as US’413 teaches that the amino acid in the formulation can be arginine, lysine, or a mixture thereof. It would have further been obvious to use the formulation in the treatment of the cancers disclosed as US’413 teaches that such methods are applicable uses of the pembrolizumab formulations disclosed. Thus, an ordinarily an ordinarily skilled artisan would have had a reasonable expectation of success.
Claims 11-12 and 25 are rejected under 35 U.S.C. 103 as being unpatentable over US 2023/0054413 A1 (Jung, Y.S., et al) 23 Feb 2023; priority to 13 Dec 2019 (corresponds to WO 2021118321 A1 2021-06-17) as applied to claim 1 above, and in further view of Technical Safety Services (TSS) (2021) What is water for injection; obtained from https://techsafety.com/blog/what-is-water-for-injection on 05/15/2026.
The teachings of US’413 are as discussed above.
As discussed above, US’413 teaches a liquid formulation of pembrolizumab that has 25 mg/mL pembrolizumab; 10 mM citrate buffer; 128 mM Arg-HCl; and 0.02% PS80; with a pH of 5.5 (8E in table 13, on page 11). Also, as discussed above, 0.02% PS80 is in w/v and is equivalent to 0.2 mg/mL.
The formulation disclosed by US’413 consists of citrate buffer, arginine, polysorbate 80, pembrolizumab, and has a pH of 5.5, which is within the claimed range of 5.0 to 5.8.
US’413 further teaches that the pharmaceutical composition is a liquid formulation and can be for subcutaneous or intravenous injection. The pharmaceutical formulation may further include an appropriate aqueous carrier suitable for injection. The aqueous carrier is a safe, non-toxic, pharmaceutically acceptable carrier that may be administered to a human, and examples thereof include water (page 4, [0032]).
US’413, however, does not disclose that the water is water for injection as recited in the instant claims.
TSS teaches that water for injection is a sterile water used to deliver medications or drugs to patients intravenously (page 3, first paragraph 1). TSS teaches that the water is prefiltered, softened, dechlorinated, and deionized and is also filtered with reverse osmosis and UV disinfection. Once this is completed, the water then undergoes a distillation process using vapor compression or multiple effect distilling (page 3, paragraph 2). All of these steps are taken to ensure that the resulting fluids are not contaminated by the bacteria and organic carbons found in everyday water. The specifications for WFI are stricter even than those for purified water. The resulting product is used by pharmaceutical manufacturers as well as doctors and other healthcare providers (page 3, paragraph 3).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the formulation disclosed by US’413 by further including water for injection as disclosed by TSS. An ordinarily skilled artisan would have been motivated to include water for injection because US’413 teaches the addition of an aqueous carrier to the composition, including water, and TSS teaches that water for injection is sterile and used in pharmaceutical manufacture and to deliver medications or drugs intravenously. An ordinarily skilled artisan would have had a reasonable expectation of success because US’413 teaches the addition of water in the pembrolizumab composition.
Regarding claim 12, the composition taught by the combination of US’413 and TSS consists of the 10 mM citrate buffer, 0.2 mg/mL PS80, 25 mg/mL pembrolizumab, and water for injection at a pH of 5.5, as discussed in detail above. In formulation also includes 128 mM Arg-HCl.
As discussed above, US’413 teaches that the amino acid used as a stabilizer can be arginine, lysine, or a mixture thereof.
US’413 further teaches that the amino acid stabilizer can be included at concentrations ranging from 0.1 to 300 mM (page 3, [0025]). The range disclosed by US’413 encompasses the amino acid amounts recited in instant claim 12, rendering the amino acid amounts obvious as it would have been obvious to use any amount disclosed by US’413 in the composition with a reasonable expectation of success. See MPEP 2144.05 I.
Additionally, the determination of the optimal amino acid and amount of amino acid(s) for use in the formulation is considered to be routine optimization where considerations for such were known in the art.
MPEP 2144.05 (II) A. states "’[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)” and "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)”.
In this case, US’413 teaches that the amino acids are added to the composition as a stabilizer and teaches that the amino acid can be arginine or lysine, or a mixture thereof. US’413 also teaches that the amino acid(s) are included at concentrations ranging from 0.1 to 300 mM. It would have been obvious to use these amino acids and ranges disclosed by US’413 and optimization that was routine in the art to determine the optimal amino acid/combination and concentration for formulation stability.
Claims 1-12 and 18-25 are rejected under 35 U.S.C. 103 as being unpatentable over Merck (2016) Keytruda Highlights of Prescribing Information, Revised: 10/2016 in view of WO 2018/204368 A1 (Sharma, M.K., et al) 08 Nov 2018.
Merck teaches that Keytruda (pembrolizumab) is a programmed death receptor 1 (PD-1) blocking antibody indicated for the treatment of melanoma, non-small cell lung cancer, and head and neck squamous cell carcinoma (HSSCC) (page 1, Indications and use; page 3, 1.1-1.3). Merck further details clinical trial information in which pembrolizumab was administered to patients with these indications (pages 8-14, 6.1). Merck further teaches methods of patient selection, dosage amounts, and preparations and administration of pembrolizumab (pages 3-5).
Merck teaches administration via injection and teaches dosage forms including an injection form comprising 100 mg/4mL (25 mg/mL) solution in a single use vial (page 5, Administration and dosage forms and strengths).
Merck teaches that the injection formulation is a sterile, preservative free, clear to slightly opalescent, colorless to slightly yellow solution that requires dilution for intravenous infusion. Each vial contains 100 mg of pembrolizumab in 4 mL of solution. Each 1 mL of solution contains 25 mg of pembrolizumab and is formulated in 1.55 mg L-histidine, polysorbate 80 (0.2 mg), sucrose (70 mg), and water for injection, USP. Merck also teaches that, in the formulation of Keytruda for injection, the composition may contain hydrochloric acid/sodium hydroxide to adjust the pH to 5.5 (page 15, 11).
Merck; however, does not disclose a formulation having citrate buffer and one or more amino acids other than histidine as recited in the instant claims.
WO’368 teaches stable formulations of antibodies against human PD-1 or antigen binding fragments thereof as well as methods for treating various cancers with the formulations disclosed. WO’368 further teaches that the formulations can be delivered by intravenous or subcutaneous administration (abstract).
WO’368 further teaches that the anti-PD-1 antibody is pembrolizumab (page 3, lines 34-35).
WO’368 teaches formulations comprising a buffer at an amount of 5 mM to 20 mM which keeps the pH in the range of about 4.5 and 6.5, and teaches that the buffer can have a pH of 5.5. WO’365 provides examples of buffers that will control the pH in this range including L-histidine and citrate (page 30, lines 3-21). WO’368 also exemplifies compositions with 10 mM buffer (page 65, Table 14).
WO’368 further teaches that the formulations comprise at least one excipient that stabilizes the formulation and that, in some embodiments, the formulation can comprise more than one stabilizer. WO’368 teaches that the anti-human PD-1 antibody formulations can comprise a stabilizer and teaches stabilizers which include about 6-8% w/v sucrose or about 3%-5% w/v L-arginine (page 25, lines 23-28). WO’368 also teaches that the presence of 3% (w/v) arginine is able to reduce the viscosity values of pembrolizumab (page 66, lines 5-14).
WO’368 also performed studies on excipients including 200 mM arginine and 200 mM L-lysine, which had similar stability results (page 65, Table 14).
WO’368 teaches that the anti-PD-1 antibody formulations are contained in a glass vial or an injection device (page 30, lines 13-15). WO’368 also teaches methods of treating cancer in a subject comprising administering an effective amount of the formulations disclosed. In some embodiments, the formulation is administered via intravenous or subcutaneous administration. WO’368 further teaches that the cancer can include melanoma, non-small cell lung cancer, classical Hodgkin lymphoma, urothelial cancer, head and neck squamous cell carcinoma, renal cancer, colorectal cancer, small cell lung cancer, solid tumors with a high level of microsatellite instability (MSI-H), primary mediastinal large B-cell lymphoma, gastric cancer, hepatocellular cancer, solid tumors with a high mutational burden, triple negative breast cancer, or urothelial cancer (page 40, line 15 – page 41, line 120).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the formulation disclosed by Merck by substituting the L-histidine with a citrate buffer at 10 mM and to substitute the sucrose with L-arginine and/or L-lysine at approximately 200 mM based on the teachings of WO’368. It would have been obvious to substitute the L-histidine with a citrate buffer at 10 mM as WO’368 teaches that buffers can be used to maintain the solution pH at 5.5 and teaches citrate buffers as an alternative to histidine buffers, suggesting analogous properties. It would have been obvious to substitute the sucrose with L-arginine and/or L-lysine at approximately 200 mM as WO’368 teaches L-arginine as an alternative to sucrose as a stabilizer in pembrolizumab formulations. Additionally, WO’368 demonstrates 200 mM of L-arginine or 200 mM of L-lysine have similar stability effects. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success.
Regarding claims 8 and 12, as discussed above, WO’368 teaches the addition of arginine as a stabilizer between about 3%-5% w/v and demonstrates both L-arginine and L-lysine at concentrations of 200 mM. 3-5% w/v of arginine is equivalent to approximately 172.22 – 287.03 mM (based on a L-arginine molar mass of approximately 174.20 g/mol).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to use these L-arginine and L-lysine amounts as a starting point for routine optimization to determine the optimal amino acid/combination thereof and amino acid concentrations for use in the formulations in order to optimize stability of the formulation.
MPEP 2144.05 (II) A. states "’[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)” and "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)”.
In this case, WO’368 teaches that the amino acids function as a stabilizer as an alternative to sucrose and tested both L-Lysine and L-arginine at 200 mM. WO’368 also suggests a range of approximately 172.22 – 287.03 mM. It would have been obvious to use these amino acids and ranges disclosed by WO’368 and optimization that was routine in the art to determine the optimal amino acid/combination and concentration for formulation stability, arriving at the instantly claimed invention.
Additionally, the L-arginine concentration of 287.03 mM is close to the instantly claimed 300 mM arginine, rendering the claimed 300 mM recited in claim 12(a) obvious as the amounts are sufficiently close as to suggest analogous properties. See MPEP 2144.05 I., which states “Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close.”
Conclusion
No claims are allowed.
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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693
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