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 .
Applicant’s remarks, filed 6/12/2026, are acknowledged and entered into the record. Applicants amended claim 1 in the remarks of 6/12/2026.
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, on 11/17/2025. Applicant's submission filed on 11/17/2025 has been entered.
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. The present application is a CIP of application 15/024,071, filed 3/23/2016, and is drawn from PCT/US2014/057234, filed 9/24/2014; and claims benefit under 35 U.S.C. 119(e) to U.S. Provisional application 61/881,857, filed 9/24/2013.
Election/Restrictions
Applicant’s election without traverse of Group I, encompassing claims 1-13, in the reply filed on 7/02/2024 is acknowledged. Claims 14 (of Group II) and claims 15-16 (of Group III) are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Groups II and III, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 7/02/2024.
Status of Claims
Claims 1 and 5-16 are pending; claims 1 and 5-13 are being examined on the merits.
Claim Rejections – Maintained
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 and 5-13 are rejected under 35 U.S.C. 103 as being obvious over Balasubramanian et al., (from IDS; US Patent 7,351,688; published 4/1/2008; henceforth '688) and Balu-Iyer et al., (from IDS; WO 2011005850; published 1/13/2011; henceforth '850), as evidenced by Frost et al., (Expert Opin. Drug Deliv., 2007, 4(4)).
The applied references have a common applicant with the instant application. Specifically, it is noted that applicant Balasubramanian (of ‘688) and applicant Balu-Iyer (of ‘850 and instant application) are the same person; see Declaration 1.132 (pg. 2, bullet point 5), filed 4/22/2025. Based upon the earlier effectively filed date of the references, each one constitutes prior art under 35 U.S.C. 102(a)(1) and 102(a)(2).
Patent ‘688 teaches compositions and methods for less immunogenic protein formulations (title). Patent ‘688 teaches that administering Factor VIII (FVIII) is a first line therapy for hemophilia, yet FVIII has a tendency to induce an immune response in 15-35% of hemophilia patients, which compromises the therapy (col. 1, lines 25-30). In order to solve this problem, ‘688 discloses complexes comprising blood Factor VIII and the phospholipid O-phospho-L-serine (OPLS), among other lipids, resulting in FVIII-OPLS (see col. 4, lines 35-48; col. 6, example 1; col. 7, examples 3 and 4), and that administration of the FVIII-OPLS complex reduced the immunogenicity against the FVIII protein in rats (col. 7, example 3). The inventors of the ‘688 patent disclose that OPLS appears to interact with FVIII, possibly shielding or masking an immunogenic epitope (col. 5, lines 35-52; col. 6, line 62 – col. 7, line 12). Thus, ‘688 teaches that combining FVIII with OPLS upon administration will reduce the immunogenicity of FVIII; however, ‘688 does not disclose administering FVIII and OPLS separately, nor does the reference suggest that doing so will induce tolerance.
Application ‘850 discloses that OPLS and other lipids induce tolerance towards antigens that are otherwise immunogenic, including FVIII (abstract; pg. 2, lines 1-23; pg. 3, lines 19-32). The authors of ‘850 disclose that the “lipid compositions provide reduced immunogenicity toward the antigen,” not merely by masking the antigen but “by altering the presentation and processing of the therapeutic protein by the immune system,” (pg. 4, lines 4-9). App ‘850 teaches that the lipids interact with the immune system to modulate Treg production, TGF-β secretion, and release of cytokines (pg. 7, lines 7-28). The reference also discloses that this strategy will be useful for inducing tolerance against an antigen, and later discloses data consistent with this theory (see Figs. 6-8). ‘850 also discloses that OPLS and antigen compositions can be administered by the subcutaneous route (pg. 5, lines 24-27). Thus, ‘850 discloses subcutaneous administration of FVIII and OPLS induces tolerance towards FVIII; however, the reference does not disclose separately administering the drugs as now claimed.
Frost teaches the art of subcutaneous drug and fluid administration (abstract). Frost teaches that following s.c. injections drugs must pass through an extracellular matrix (ECM) in order to reach the vascular compartment (pg. 427, section 1.1); and that the ECM controls the diffusion and bulk fluid flow (section 1.1), and is a significant barrier to the effective s.c. delivery of many drugs because the ECM is not a fluid, but rather a solid matrix of collagenous fibrils embedded within a glycosaminoglycan-rich viscoelastic gel that buffers convective forces (abstract). Frost teaches large proteins such as monoclonal antibodies (150 kDa) may take several days to reach maximal levels in plasma, and that for these biologics, significant amounts of injected protein may not escape from the local tissue intact; one such example is Factor VIII (pg. 428, col. 1, para. 3). Thus, Frost teaches that s.c. injections would be expected to be present in the s.c. space for minutes to hours (and days for larger molecules) after injection. Further, Frost teaches the radius of injection spread (pg. 435, figure 4), whereby the average dispersion area beads < 200 nm in size was approximately 50 mm2 (Fig. 4d); which is equivalent to ~2 inches (25.4 mm per inch). Taken together, the teachings of Frost would provide a skilled artisan with a reasonable expectation that separate s.c. injections of two compositions into the same local area (i.e. within 2 inches) and within 30 minutes, would be overlapping in the tissue, and provide ample opportunity for the 2 compositions to co-occupy the same tissue space.
It would have been obvious to one of skill in the art to modify the method of inducing immune tolerance comprising administering a single composition of FVIII and OPLS to instead comprise local overlapping injections of a FVIII composition and a separate OPLS composition. One would have been motivated to do so given the knowledge that when FVIII is presented in association with OPLS, it can reduce immunogenicity to FVIII, as taught by ‘688; and it generates immune tolerance to FVIII, as taught by ‘850. There would have been a reasonable expectation for success given the teachings of Frost et al. that injection of either a FVIII composition or a OPLS composition would reside in the s.c. ECM space, within 2 inches, for at least 30 min, thus allowing for the co-occupation of the same space; and also allowing for the OPLS-mediated altered presentation and processing of the antigen to the immune system, as taught by ‘850. Thus, the invention as a whole was prima facie obvious to one of skill in the art at the time the invention was made.
MPEP section 2144.04 (V)(B) and (C) teaches obviousness in “making separable” compositions taught as combined, or vice versa. The court held that separating two components that were previously taught as combined was obvious, and that if it were considered desirable to separate the components, it would be obvious to do so (2144.04(V)(C)). However, the court also found that in making an invention integral, if the art perceived a need for mechanisms, and the integration of the components eliminated that perceived need, then making the invention integral is not obvious (2144.04(V)(B)). Here, neither the claims nor the disclosure present evidence that separating the components of the composition of ‘850 into two separate, but overlapping, administrations circumvents a pitfall of, or adds a significant advantage over, the prior art. Thus, there is no perceived need for alternate mechanisms of administration, whereby each component is administered separately, into the same space.
Regarding claims 1, 5 and 12-13, Section 2143(I) provides examples of rationales that support a conclusion of obviousness. These would include applying alternative known techniques to similar methods for the same purpose or to yield predictable results. As ‘688 teaches OPLS+FVIII can reduce immunogenicity of the antigen, ‘850 teaches that OPLS can “alter presentation of” and subsequently impart immune tolerance towards an antigen, and Frost teaches that it is reasonable to expect that separate injections of OPLS compositions and antigen compositions would co-occupy the same tissue space, within 2 inches and for > 30 min after administration, it is obvious for a skilled artisan to administer the OPLS and the antigen as separate injections at least 1 minute apart (re. claim 1); including whether the co-injections occur within 10 minutes (re. claim 12), or within 5 minutes (re. claim 13). ‘850 teaches that the injections may be subcutaneous (re. claim 5). Thus, claims 1, 5 and 12-13 are made obvious over Patent ‘688 and Application ‘850, as evidenced by Frost.
Regarding claims 6-11; ‘688 teaches the concentration of OPLS can be 5 or 20 mM (col. 6, example 1) thus makes obvious instant claim 7, wherein the concentration may be 20 to 300 mM. Application ‘850 teaches the concentration of OPLS can be from 1 to 100 nM, but uses 10 mM in Example 2 (pg. 25, line 18), leading to some confusion over the range of concentrations that are embodied. Claim 6 recites a concentration of more than 20 mM, whereas ‘688 teaches the concentration of OPLS can be 20 mM. Section 2144.05 of the MPEP discusses similar and overlapping ranges. Section 2144.05(I) states “a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close.” Similarly, 2144.05(II)(A) states “Where 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.” Thus, while ‘688 teaches concentrations of OPLS of 5 or 20 mM, it would be obvious for a skilled artisan to use for example, 25 mM OPLS, to achieve predictable results; especially in view of altering the administration to be separate overlapping injections, whereby a higher concentration of OPLS may be warranted. As 25 mM (or even 21 mM) OPLS would be “more than 20 mM” OPLS, claim 6 is rejected as obvious over ‘688 and ‘850, in view of Frost. Regarding claim 8, ‘688 teaches the FVIII-OPLS composition in a buffer comprising 300 mM NaCl and 5 mM CaCl2 (col. 6, example 1), which would be a solution with > 300 mmole/kg osmolality. Regarding claim 9, ‘688 teaches a single administration of FVIII-OPLS (col. 7, example 3), which would be once weekly for one week. Regarding claim 10, ‘688 teaches that the antigen is a blood factor, specifically Factor VIII (col. 1, lines 21-22). Regarding claim 11, ‘850 teaches the antigen may be a peptide, or polypeptide, or proteins (pg. 6, lines 22-23); whereby such proteins may be FVIII or insulin (pg. 6, line 29).
Response to Arguments
Applicant's arguments filed 6/12/2026 have been fully considered but they are not persuasive. Applicants contend that a prima facie case of obviousness requires that each claim feature must be present, and an artisan must have a motivation to combine references (remarks, pg. 5, para. 5). Applicants contend that the cited references do not teach the specific sequential administration protocol recited, whereby the OPLS first primes the immune system, followed by antigen administration (pg. 6, paras. 1-2). Applicants contend that Frost does not teach the protocol and does not provide a reasonable expectation of success from separate dosing, nor provide a motivation to modify the teachings (pg. 6, para. 3; pg. 7, para. 1). Applicants further contend that a “making separable” analysis is misplaced because the claims require a specific order of administration, and thus is not a simple separation of components (pg. 7, para. 3).
Regarding applicant’s contention that a prima facie obviousness requires that each claim feature must be present, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). The cited references, the ‘688 patent and ‘850 application, teach administering a composition of OPLS and FVIII induces immune tolerance to FVIII. There is no advantage to separate the composition into distinct injections. The ability of OPLS to “prime the immune system” is an inherent property of the composition. As detailed in the office action of 12/31/2025, Example 14 (specs., pg. 37, para. 0150) shows that a composition comprising OPLS+FVIII is more effective at inducing immune tolerance than separating the OPLS and FVIII into distinct administrations, 5 minutes apart in the same location. Thus, the administration of OPLS + FVIII in a single composition is the invention for inducing immune tolerance, of the combination of ‘688 and ‘850. To separate the OPLS and FVIII into two distinct administrations, within 1 minute and within 2 inches of the same tissue, is making the invention of ‘688 and ‘850 dis-advantageous. The examiner acknowledges that the separate administration regime successfully induces immune tolerance compared to FVIII control, but it is less effective compared to a OPLS + FVIII composition as a single administration. Thus, applicants do not demonstrate a benefit or advantage for separating the elements of the composition into two injections, rather the claimed protocol is dis-advantaging the patented invention.
Regarding the “making separable” rationale for obviousness of MPEP 2144.04(V)(B) and (C), the motivation for doing so is inherent “if it were considered desirable for any reason (to separate)…it would be obvious” to do so. As described above, the OPLS + FVIII single composition administration was more effective at inducing immune tolerance, therefore any “priming” effect of OPLS on the immune system is encompassed in administering the composition, and does not require a distinct administration of OPLS only, before a second distinct administration of antigen, within 10 minutes into the same tissue location. That is, in the instant case, the examiner considers the induction of immune tolerance to be the result effective variable of the methods, not “priming”. Thus, applicant’s arguments that applying a “specific order of administration” is not a simple separation of components, is unpersuasive. The examiner considers the separation of OPLS and antigen into separate administrations, into the same tissue in spatial and temporal proximity, to induce the same effect, whereby the effect is less advantageous than when the components are administered as a single composition, to be an obvious simple separation of components, with no patentable distinctness, and no technological advantage, over the inventions of ‘688 and ‘850.
Applicants contend “this priming mechanism is not taught, suggested or even expected by the cited reference,” (remarks, pg. 7, para. 2). However, the “priming mechanism” is not claimed. Nor is it claimed that the OPLS must have vacated the tissue space when the second injection of antigen occurs, (see remarks, pg. 6, para. 3). It is not clear, mechanistically, what the “priming” effect is; this is presumably why such effect is not claimed. Given that the OPLS+FVIII composition is more efficacious in inducing immune tolerance than separate injections of OPLS and FVIII, even into the same tissue 5 minutes apart, it is obvious that administering the OPLS/FVIII composition encompasses any priming mechanism of OPLS necessary to induce immune tolerance. It is also clear that the OPLS does not have to have cleared the tissue before the antigen (FVIII) is administered. If anything, the results of Example 14 suggest that the more OPLS has cleared, the less effective it is at inducing antigen specific immune tolerance. This further supports that the most advantageous method for inducing immune tolerance using OPLS and an antigen, is to administer them in a single composition, as taught in ‘688 and ‘850.
Regarding applicants contention that Frost does not teach or suggest administering OPLS and an antigen, that Frost does not provide a reasonable expectation for success for inducing immune tolerance, and Frost does not provide motivation to modify the teachings; Frost was not relied on for obviousness or motivation. Frost was evidentiary to the reasonable expectation for success of the combination of ‘688 and ‘850, which makes obvious the instant methods of separating a known composition into two separate administrations, in order to obtain predictable results. The support for the obviousness over ‘688 and ‘850 is found in MPEP 2143(I), as well as the “making separable” obviousness rationale of MPEP 2144.05. Thus, to argue that Frost does not teach the claim limitations or provide a motivation to combine references, is to attack Frost individually, when the obviousness was based on the combination of ‘688 and ‘850. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Frost provides evidentiary support that an injection of OPLS would linger in the tissue, within 2 inches and for < ~30 min. Thus, under the limitations of the 2 separate injections of the instant methods, there is a reasonable expectation that OPLS and antigen (FVIII) would co-occupy the same space when given 1-10 min apart into the same location. However, this isn’t the primary basis of the obviousness rejection. The motivation with reasonable expectation for success, is to induce immune tolerance, and is provided by the ‘688 and ‘850 references of the rejection. The obviousness of separating a single injection of a composition comprising OPLS + FVIII into two separate injections is supported by the rationales of MPEP 2143(I) and the “making separable” obviousness rationale of MPEP 2144.05. These obviousness rationales speak specifically to arbitrary differences in design, range, form or method, whereby the differences are common knowledge in the art and do not generate any advantage to the invention, i.e. obtaining “predictable results.” The differences between the instant claims and the prior art amount to separating administration of a single composition comprising two components into two “overlapping” administrations of each component. The motivation to combine is to induce immune tolerance as taught by ‘688 and ‘850, and does not rely on Frost. MPEP 2143, 2144.05 and Frost, support the obviousness of separating a single composition into two compositions, with no advantage to doing so. The only way to make such arbitrary design difference non-obvious is if they impart a particular advantage. Here, the separation of a single composition comprising OPLS/FVIII into two separate administrations of OPLS and FVIII, provides no advantage over the single composition taught by the combination of ‘688 and ‘850; therefore it is obvious to do so and need not be recited in any of ‘688, ‘850 or Frost. The “priming effect”, whatever that may be, or if it even occurs at all, is not recited in the claims. The two injections are being administered in the same location within 10 minutes of each other. Frost supports that they are therefore likely “overlapping” in the tissue. MPEP 2143 and 2144.05 supports that, without evidence of any particular advantage for separating the components into separate injections, it is obvious to do so. The instant specifications do not report any advantage; rather Example 14 teaches it is disadvantageous to separate the injections versus administering a single composition comprising both OPLS and antigen (FVIII), as the induction of immune tolerance is decreased with separate administrations. Therefore the methods of the instant claims are encompassed and made obvious by the invention of the combination of ‘688 and ‘850, whereby it is obvious, though disadvantageous, to simply separate the components into separate, overlapping, administrations as a means of reciting an alternative design to the same methods, practiced for the same purpose. Applicant’s arguments are not persuasive and the rejections are maintained.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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.
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/JAMES RYLAND MELCHIOR/Examiner, Art Unit 1644
/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642
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