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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 3/16/2026 has been entered.
Claims 1-4, 7-14, 17-18, and 52-56 are now pending. Claims 1, 18, and 53 are amended. 35 U.S.C. 112(b) is hereby withdrawn in view of amendments.
Claims 1-4, 7-14, 17-18, and 52-56 are currently being examined.
Maintained Arguments
(Arguments Addressed)
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).
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, 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, 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.
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, (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, and (3) Brych teaches that the composition allows for stable solutions to allow for ease of administration and longer shelf lives of products. 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, 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, becausechanges/formation in HMWS after long term storage, one of skill in the art could have produced a liquid composition having a variation in HMWS of 5.0% or less after storage at 1 month at 40ºC based on the teachings of Brych, with a reasonable expectation of success.
Response to Arguments
Applicant argues that the prior provides: (a) No motivation to select Formulation K: Applicant argues that there is no motivation to select formulation K, as Figure 1 of Brych shows that Formulation K exhibits significantly higher levels of “already formed aggregates” and HMWS; (b) No motivation to select histidine: Applicant argues that Brych teaches away from selecting histidine and (c) No motivation to select a lower concentration of an anti-RANKL antibody:
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. 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.
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.
Conclusion
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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.
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/SARAH A ALSOMAIRY/Examiner, Art Unit 1646
/Zachariah Lucas/Supervisory Patent Examiner, Art Unit 1600
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