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
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 6/30/2026 has been entered.
Claims 1-4, 7-14, 17-18, and 52-56 are now pending. Claims 1, 3-4, 9-14 are amended. Claims 1-4, 7-14, 17-18, and 52-56 are currently being examined.
New Rejection
(Necessitated by Amendments)
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim(s) 1-4, 7-14, 17-18, and 52-56 remain rejected under 35 U.S.C. 103 as being unpatentable over Brych et al (WO2018200918 A1; Published 11/1/2018; of record), in view of Kang et al (Rapid Formulation Development for Monoclonal Antibodies, Published 4/12/2016) and Gwee (WO2015134406 A1; Published 9/11/2015).
Brych teaches a liquid composition, which comprises an anti-RANKL antibody, has a pH of 5-7 and is free of an acetate. Brych teaches that the liquid composition is free of both a succinate and a glutamate. [0004-0007, Table 1, Formulation K] Brych teaches that the liquid composition comprises amino acids, such as histidine 75 mM, arginine, lysine, phenylalanine, or tryptophan. [0009, 00102, 00104]. Brych teaches that the liquid composition also comprises a tonicity modifier, a surfactant, and a buffer. [0011-0012] Brych teaches that the tonicity modifiers are sugars, or sugar alcohols, such as sorbitol. Brych teaches that that the sorbitol can be used 1-5% w/v, and that these sugars can be used to protect proteins from aggregation and providing freeze/thaw stability. [00124-0125, 0100-0103] Brych teaches that the surfactant can be polysorbate 20 and polysorbate 80, and that these agents reduce interfacial tension and mitigate formation of large proteinaceous particles. Bryce teaches that that the liquid composition comprises 0.001 to 1% w/v surfactant, polysorbate 20 or polysorbate 80. [0118-01120, 00156] Brych teaches that the liquid composition is denosumab, and comprises 50 mg/ml to 80 mg/mL. Brych further teaches that the liquid composition is applicable to an injection agent comprises 60 mg/mL anti-RANKL antibody or 70 mg/ml anti-RANKL antibody. [0004, 0054, 0090-0092] [00120] Bryce teaches that the formulation can be buffered that does not include acetate, glutamate, or succinate, and may be self-buffered. [0096, Table 1] Brych teaches a liquid composition, which comprises an anti-RANKL antibody, has a pH of 5-7 and is free of a succinate. [Table 1, Formulation K: Self-buffered, sorbitol (5% w/v), polysorbate 20, pH 5.2]
Brych teaches that the composition allows for stable solutions to allow for ease of administration and longer shelf lives of products. [0049] Brych teaches producing stabilized formulations that have reduced formation of high molecular weight species (HMWS) after at least 1 month of storage at 37ºC, and after 2 to 3 years, wherein changes in HMWS formation are less than 5%. Brych teaches the importance of monitoring formation of HMWS during storage and motivation to reduce HMWS formation [0019] Figures 1, 2, 4, 6, 8, 9, 11, 13-15, 31, 39, and 41-43; [50] [56-57] [0063-0067] Brych demonstrates testing formulations for HMWS stability that were stored at a temperature of 40°C for one month [0163, Table 7A]
However, Brych does not demonstrate: (1) the exact liquid composition comprising 5 to 40 mM histidine, and (2) that the liquid composition after being stored at 40 °C for four weeks, and has a variation in high molecular weight at 5.0% or less of the formulation free of acetate.
Kang teaches that formulation development of monoclonal antibodies are an important aspect to product development and a critical path to successful clinical manufacturing and stability studies. [pg 2, 1st paragraph] Kang teaches that one of the most common buffers includes histidine at a concentration between 10-50 mM. [pg 5] Kang teaches that histidine had a substantial positive effect in inhibiting formation of aggregates. [pg 7]
Gwee teaches stable protein formulations which includes (a) an antibody, (b) pH 5.2, (c) histidine (mM), (d) free of acetate [0026, Table 2, Formulations 3 and 4].
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to produce a liquid composition comprising: (1) an anti-RANKL antibody (50 mg/ml – 80 mg/ml), (2) pH 5-7, (3) histidine (5-40 mM), (4) an amino acid such as arginine, (5) a sugar such as sorbitol, (6) polysorbate 20 or polysorbate 80, and is free of an acetate, glutamate, and succinate in the method of Brych. One would have been motivated to, and have a reasonable expectation of success, because: (1) Bryce teaches and demonstrates a liquid composition comprising an anti-RANKL antibody, 50 mg/ml to 80 mg/mL, sorbitol, and a pH between 5-7, and that this formulation does not contain acetate, glutamate, and succinate, (2) Bryce teaches that the liquid composition comprises a surfactant, such as polysorbate 20 and 80 to reduce interfacial tension, a buffer, and amino acid aggregate inhibitors, such as amino acid arginine, and histidine, (3) Brych teaches that the composition allows for stable solutions to allow for ease of administration and longer shelf lives of products, (4) Kang teaches that one of the most common buffers includes histidine at a concentration between 10-50 mM and Kang teaches that histidine had a substantial positive effect in inhibiting formation of aggregates, and (5) Gwee teaches stable protein formulations which include histidine at a concentration of 20 mM.
Brych recognizes the need in the art to produce stable liquid composition comprising anti-RANKL antibodies. Given the recognized need to produce these stable liquid compositions comprising anti-RANKL antibodies, the known methods and agents to create stable liquid compositions and known functions of these agents, known methods of adding histidine to produce stable antibodies at a concentration around 5-40 mM, one of skill in the art could have produced the instantly claimed liquid composition in the methods of Brych, with a reasonable expectation of success.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed for Brych to provide a liquid composition that has a variation in high molecular weight of 5.0% or less after storage for four weeks at 40ºC. One would have been motivated to, because
Response to Relevant Arguments
Applicant argues that the prior provides:
The suggested modification is based on hindsight reconstruction:
No motivation to modify Byrch: Applicant argues there is motivation to modify Brych to arrive at the composition of claim 1. Applicant argues that Brych generally teaches "high-concentration" denosumab formulations containing denosumab at concentrations significantly higher than those recited in amended claim 1 and further employs different excipients at different concentrations. Amended claim 1 recites a liquid composition comprising "50 mg/mL to 80 mg/mL anti-RANKL antibody and 5 to 40 mM histidine, has a pH of 5 to 7, and is free of an acetate."
Applicant argues that The Office relies on paragraphs [0004], [0054], and [0090]-[0092] of Brych to assert that Brych describes a 60 or 70 mg/mL denosumab formulation. Applicant argues that that conclusion is based on selectively combining isolated disclosures from separate portions of the reference rather than considering Brych as a whole. Applicant argues that paragraphs [0090]-[0092] merely provide a generic, laundry-list enumeration of potential antibody concentrations without any specific formulation or technical basis. Applicant argues that Brych does not specifically describe applying the above antibody formulation composition to a low-concentration denosumab formulation.
Applicant argues there is no motivation to select histidine: Applicant argues that Brych consistently relies on acetate based buffers and treats acetate as a standard formulation component. Applicant argues that there is no motivation to use lower histidine concentrations, and Brych’s only histidine example comprises 75 mM histidine (Formulation 31).
Applicant argues there is no reasonable expectation of success: Applicant argues the Office fails to address Formulation 31 of Brych, which is the only formulation comprising denosumab and histidine. Brych's Formulation 31 employs a relatively higher concentration of histidine (75 mM) and denosumab (120 mg/mL), and Formulation 31 contains acetate (see Table 8A of Brych). Applicant argues that Brych provides no indication that histidine could function as the sole buffering system and Brych is silent regarding an acetate-free formulation comprising denosumab and histidine. Applicant argues that this creates uncertainty as to whether acetate removal would succeed for a formulation comprising higher concentrations of denosumab and histidine.
The results are unexpected: Applicant argues that the in Brych the sole histidine containing formulation employs a relatively higher concentration of histidine (75 mM) and denosumab (120 mg/ml). However, Example 3 of the specification demonstrates that the stability of the composition increases as both the histidine concentration and the protein (antibody) concentration are kept lower. Applicant argues that this unexpected stability at lower concentrations directly contradicts Brych’s teachings of higher antibody concentration and higher histidine concentration.
Applicant’s arguments have been considered but are not persuasive. As noted in prior office actions, Brych teaches a liquid composition comprising an anti-RANKL antibody and histidine, and has a pH of 5-7 and is free of an acetate. The amended concentration of histidine has not been presented before in the claims and is addressed in the above 103 rejection.
Although Brych does not specifically exemplify the liquid composition comprises histidine, Brych does teach that histidine is a component of the liquid composition. Brych exemplifies a liquid composition without acetate, glutamate or succinate. [See Table 1, Formula K. Self-buffered, sorbitol (5% w/v), polysorbate 20, pH 5.2] Brych also teaches that the liquid composition is applicable to an injection agent comprises 60 mg/mL anti-RANKL antibody or 70 mg/ml anti-RANKL antibody. Contrary to arguments, Brych does not need to provide a working example of the liquid composition comprising histidine. MPEP 2164.02 states that: The specification need not contain an example if the invention is otherwise disclosed in such manner that one skilled in the art will be able to practice it without an undue amount of experimentation. In reBorkowski, 422 F.2d 904, 164 USPQ 642, 645 (CCPA 1970). Regarding the Applicant’s arguments that Brych teaches “away from a composition comprising histidine.”
MPEP 2145 states the following:
2145 Consideration of Applicant’s Rebuttal Arguments and Evidence [R-01.2024]
D. References Teach Away from the Invention or Render Prior Art Unsatisfactory for Intended Purpose
1. The Nature of the Teaching Is Highly Relevant
A prior art reference that "teaches away" from the claimed invention is a significant factor to be considered in determining obviousness. However, "the nature of the teaching is highly relevant and must be weighed in substance. A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use." In re Gurley, 27 F.3d 551, 553, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994) (Claims were directed to an epoxy resin based printed circuit material. A prior art reference disclosed a polyester-imide resin based printed circuit material, and taught that although epoxy resin based materials have acceptable stability and some degree of flexibility, they are inferior to polyester-imide resin based materials. The court held the claims would have been obvious over the prior art because the reference taught epoxy resin based material was useful for the inventor’s purpose, applicant did not distinguish the claimed epoxy from the prior art epoxy, and applicant asserted no discovery beyond what was known to the art.).
Furthermore, "the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). See also UCB, Inc. v. Actavis Labs, UT, Inc., 65 F.4th 679, 692, 2023 USPQ2d 448 (Fed. Cir. 2023) ("a reference does not teach away if it merely expresses a general preference for an alternative invention but does not criticize, discredit or otherwise discourage investigation into the invention claimed.") (internal quotations omitted) (quoting DePuy Spine, Inc. v. Medtronic Sofamor Danek, Inc., 567 F.3d 1314, 1327 (Fed. Cir. 2009)); and Schwendimann v. Neenah, Inc., 82 F.4th 1371, 1381, 2023 USPQ2d 1173 (Fed. Cir. 2023) ("Although Oez [the prior art] used a white pigment with a cross-linking polymer, it does not discourage a skilled artisan from using the white pigment without a cross-linking polymer or lead the skilled artisan in a direction divergent from the path taken in the Appealed Patents. Thus, Oez's disclosure is substantial evidence that supports the Board's finding that Oez does not teach away from the proposed combination.").
In this instant case, Brych specifically teaches the use of histidine with charged side chains, such as histidine. [00102] Brych further teaches that the specific histidine formulation could be biased from dialysis process, longer duration spent at pH 4., and the titration of the formulation with dilute NaOH. Brych teaches that “Formulation K” contained lower levels of HWMS. [0165] Thus, Brych does not teach away from using histidine, rather teaches that the composition will still perform and act as a stabilizer. However, the new prior art presented in this office action also teach that the addition of histidine at the claimed concentration is known and the benefits of adding histidine to prevent protein aggregation is well known in the art.
With regards to selecting lower concentration of anti-RANKL antibody: the instant claims state the liquid composition which comprises 50 mg/ml to 80 mg/ml anti-RANKL antibody. Brych specifically teaches that the liquid composition is applicable to an injection agent comprises 60 mg/mL anti-RANKL antibody or 70 mg/ml anti-RANKL antibody. [see 0090-0092]
Brych recognizes the need in the art to produce stable liquid composition comprising anti-RANKL antibodies. As recited in the above 103 rejection, given the recognized need to produce these stable liquid compositions comprising anti-RANKL antibodies, the known methods and agents to create stable liquid compositions and known functions of these agents, one of skill in the art could have produced the instantly claimed liquid composition in the methods of Brych, with a reasonable expectation of success.
With regards to unexpected results, the MPEP states:
MPEP 716.02(d) states: Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.” In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980) (Claims were directed to a process for removing corrosion at “elevated temperatures” using a certain ion exchange resin (with the exception of claim 8 which recited a temperature in excess of 100C). Appellant demonstrated unexpected results via comparative tests with the prior art ion exchange resin at 110C and 130C. The court affirmed the rejection of claims 1-7 and 9-10 because the term “elevated temperatures” encompassed temperatures as low as 60C where the prior art ion exchange resin was known to perform well. The rejection of claim 8, directed to a temperature in excess of 100C, was reversed.). See also In re Peterson, 315 F.3d 1325, 1329-31, 65 USPQ2d 1379, 1382-85 (Fed. Cir. 2003) (data showing improved alloy strength with the addition of 2% rhenium did not evidence unexpected results for the entire claimed range of about 1-3% rhenium); In re Grasselli, 713 F.2d 731, 741, 218 USPQ 769, 777 (Fed. Cir. 1983) (Claims were directed to certain catalysts containing an alkali metal. Evidence presented to rebut an obviousness rejection compared catalysts containing sodium with the prior art. The court held this evidence insufficient to rebut the prima facie case because experiments limited to sodium were not commensurate in scope with the claims.).
In this instant case, the claimed liquid composition comprising the agents is known in the art as demonstrated above. As stated above, one of skill in the art could have pursued adding histidine and the antibody at the claimed concentrations based on the disclosure of the cited references. Thus, the results are expected.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SARAH A ALSOMAIRY whose telephone number is (571)272-0027. The examiner can normally be reached Monday-Friday 7:30 AM to 5:30 PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gregory Emch can be reached at (571) 272-8149. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SARAH A ALSOMAIRY/Examiner, Art Unit 1646
/Zachariah Lucas/Supervisory Patent Examiner, Art Unit 1600
Prosecution Insights