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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 11/17/2025 has been entered.
Applicants amended claim 5 in the remarks of 11/17/2025.
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 Claims 14 (of Group II) and claims 15-16 (of Group III) are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Groups II and III, there being no allowable generic or linking claim.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 0.5 minutes 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 11/17/2025 have been fully considered but they are not persuasive. The declaration under 37 CFR 1.132 filed 11/17/2022, is acknowledged.
Applicants contend that the combination of references do not teach all the limitations of the claims (remarks, pg. 5, para. 6) with motivation to combine and a reasonable expectation for success. Applicants contend that ‘688 teaches reducing immunogenicity; Balu (i.e. ‘850) teaches tolerance induction via a single injection of a composition, and does not teach making the injection separate (remarks, pg. 5, para. 7); and Frost does not bridge the gap (pg. 6, para. 1). Specifically, applicants cite the Rule 1.132 Declaration (remarks, pg. 6, para. 2), which contends that the induction of tolerance via sequential administration is surprising due to the expectation that co-localization of the OPLS and antigen are required. Applicants also contend that the “making separable” rationale, of MPEP 2144.04, does not apply because nothing in the cited references suggests separate injection would induce tolerance (remarks, pg. 6, para. 4), and Frost fails to provide motivation, nor a reasonable expectation of success, for the induction of immune tolerance from separate dosing (pg. 7, para. 1). Further, applicants contend that the biological arts are unpredictable; that because “after a period of time in which the OPLS has potentially cleared from the system”, inducement of immune tolerance may still occur, it is indeed unexpected and counterintuitive (pg. 7, para. 2). Thus, applicants contend that obviousness cannot be applied when physiological activity is unpredictable and, in this case, the success of separable injections was unpredicted (pg. 7, para. 2).
First, the examiner would like to acknowledge the Rue 1.132 Declaration from 4/22/2025, which differentiates “reducing immunogenicity” from “inducing immune tolerance.” In the Rule 1.132 Declaration of 4/22/25, the instant inventor (who is also an inventor on the reference patent ‘688) declares that the ‘688 patent describes reducing the immunogenicity of Factor VIII by a mechanism of shielding the immune dominant epitopes from the immune system (Rule 132 Declaration, bullet point 6). Further stating that “it is important to note that reduction in immunogenicity by shielding the epitope as a result of binding and immune tolerance are not the same thing; immune tolerance, actively engaging the immune system, is antigen specific where shielding is not.” Thus, applicants contend that, when administered as separate compositions, it is unlikely that binding between the antigen and OPLS is occurring, and thus unlikely that “shielding” as a mechanism of reducing immunogenicity is the means of inducing immune tolerance of the instant claims (Rule 132 Declaration, bullet point 7). Examiner acknowledges this point. The instant claims are drawn to a method of inducing immune tolerance, and therefore discussion of whether the two agents are complexed, or whereby the OPLS is providing shielding of the antigen, is irrelevant to the rejections of the instant claims. As described above, patent ‘850 teaches that injection of a composition of OPLS and antigen induces immune tolerance. Applicants contend that the combination of references do not provide motivation or a reasonable expectation for success because each reference teaches a different aspect, and none of the references, individually, provide motivation or reasonable expectation for success for the combination. 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). Patent ‘688 teaches a composition of OPLS and antigen reduces immunogenicity towards that antigen; Patent ‘850 teaches the same composition also induces immune tolerance towards the antigen. Thus, the combination of ‘688 and ‘850 make obvious administering the composition for the purpose of inducing immune tolerance. The motivation is to induce antigen-specific immune tolerance instead of reducing immunogenicity; and, given that both ‘688 and ‘850 teach OPLS + antigen compositions, and ‘850 teaches the compositions induce immune tolerance, there was a reasonable expectation for success. Frost merely provides evidence that separating the agents into two separate injections, administered in both temporal and spatial proximity, would behave similarly to administering the agents together in a single composition. Given that the goal is not to reduce immunogenicity, whereby the agents must be complexed to provide “shielding” of the antigen, there is no need for the agents to be complexed, in a composition or in the tissue. This further supports Frost, in evidencing that separating a composition of two agents into two injections into the same space, in close temporal proximity, provides a reasonable expectation for success compared to when the two agents are administered in the same composition. Thus, the combination of ‘688, ‘850 and Frost provides both motivation and a reasonable expectation for success, and thus makes obvious a method of inducing immune tolerance by administering two separate injections of OPLS and antigen into the same tissue in temporal proximity to one another.
Regarding applicant’s Rule 1.132 Declaration of 4/22/25 and the contention that induction of tolerance via sequential administration is surprising due to the expectation that co-localization of the OPLS and antigen are required. First, the examiner points out that the mere possibility that something might not work does not make it unexpected when it does work. The inventor describes that given that charged small molecule OPLS is expected to clear faster, and likely there may not be enough OPLS left at the injection site by the time the antigen arrives. This is speculation; it is not proof that OPLS is absent from the site at the time of the second injection, which would occur 30 seconds later, as recited in claim 1. Further, the claims as written do not encompass this scenario; that is, they do not require that OPLS is absent from the tissue at the time of the second injection. In fact they allow the two injections to occur within as little as 30 seconds. The inventor goes on to describe a proposed mechanism whereby “prior administration of OPLS creates a tolerogenic milieu in the cutaneous space promoting secretion of regulatory cytokines such as TGFβ, that help generate semi-matured dendritic cells that are predisposed to tolerance; and engagement of macrophages with OPLS in sub-cutaneous spaces leads to transfer of the antigen in tolerogenic manner by these primed macrophages,” (remarks, pg. 6, para. 2). These remarks support that administering the OPLS and antigen into the same tissue space is necessary. That is, that the OPLS is “priming” the cells occupying that tissue space for inducing immune tolerance to the antigen, which is separately injected into the same space whereby the tissue cells are OPLS-primed. This is reasonably expected to occur if the two agents are administered in the same composition, as taught by ‘688 and ‘850; and Frost further evidences that two separate injections, in spatial and temporal proximity, would behave similarly to a single injection of a composition comprising two agents. The instant claims require that the two injections occur in spatial and temporal proximity, consistent with injection of a composition. For example, the claims are not drawn to injecting OPLS into the right leg and injecting antigen into the left leg for promoting induction of immune tolerance towards that antigen; nor do the claims encompass injecting OPLS first, and then, 24-48 hours later, injecting antigen. The applicant’s claims, as well as the applicant’s arguments and description of mechanism all support that the injections, while being separate, occur in spatial and temporal proximity to each other, and this is necessary for the effect. This effect would also occur if the two agents were administered in a single composition. Thus, the result of inducing immune tolerance when making the agents separable is not surprising nor unexpected, when they are provided in temporal and spatial proximity to one another. Rather, this appears to be a design choice and not a fundamental change in the claimed methodology, as there is no indication of what is fundamentally different between injecting a composition of two antigens, as taught by the combination of ‘688 and ‘850, versus two injections in spacial and temporal proximity to one another, of the instant claims, for inducing immune tolerance. As discussed above, it is clear that the two agents do not need to be complexed, in solution or in tissue, for the effect of immune tolerance to occur. Therefore, separating the two agents into two injections, administered in spatial and temporal proximity to one another, and resulting in immune tolerance to the antigen, is not considered surprising nor unexpected.
Regarding the obviousness of making separatable, of MPEP 2144.04, the applicants contend that the examiner must take care to ensure that the rationale is explained and shown to apply to the facts at hand, that nothing in the cited references suggests separate injections would induce tolerance, and that for motivation, there must be more than a mere possibility, and the combination of references do not yield more than a mere possibility (remarks, pg. 7).
In response to applicant's argument that nothing in the cited references suggests separate injections, 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 examiner has described above that the applicants remarks regarding mechanism, and the scope of the claims, do not differentiate why a composition comprising the two agents does not induce immune tolerance, while separating them into two injections does induce immune tolerance. Instead, ‘850 teaches that providing a composition of OPLS and antigen does induce immune tolerance towards the antigen, and that induction of immune tolerance can be measured by an increase in TGFβ levels (pg. 2, lines 5-6); thus supporting the same mechanisms of priming as described in the Rule 1.132 Declaration from the inventors. Thus, it is not a “mere possibility” that the combination of references would work, it is very reasonable to expect that they would work because ‘850 teaches the composition works. There is nothing in the references that teaches away from the composition working, nor that the composition imparts any particular property for inducing immune tolerance that isn’t also present when two separate injections are administered instead. If anything, the instant specifications teach that separating the OPLS and antigen into two injections was less effective at inducing immune tolerance compared to administer a single composition comprising both. For reference, example 14 (instant specs., pg. 37, para. 0150) shows that the immunogen response to antigen GAA two weeks after previous administration of a) control TRIS, b) combined GAA and OPLS or c) OPLS injection followed 5 min later GAA injection into the same site, resulted in an immunogenic response of 8775 units in the control, 895 units in the combined group and 1884 units when separately administered (para. 0150). In either case the combination of GAA and OPLS reduced immunogenicity, but separate administrations, 5 min apart, appeared less effective, but effective nonetheless, than when the agents were combined prior to injection (Fig. 27). This is the only example that properly compares administration of an antigen-OPLS composition vs separate administrations of antigen composition and OPLS composition. As the examiner has described above, it is not considered unexpected nor surprising that two separate injections induces immune tolerance similarly, if not less effectively, than administering a single composition comprising both agents. As both administration regimes seem to engage the same TGFβ mechanisms for inducing immune tolerance, there is no evidence that giving two separate injections imparts any benefit, or solves any need in the art, compared to administering the composition comprising the two agents. Frost further supports the reasonable expectation for success by evidencing that two separate injections, in spacial and temporal proximity, would behave similarly in tissue compared to a single composition comprising both agents- wherein there is no need for the agents to be complexed. The examiner has clearly articulated that there was a reasonable expectation for success for separate injections to work similarly as compared to a single injection of a composition of both agents, and that there was no unexpected benefit or result derived from separating the agents into two injections. MPEP 2144.04 makes clear that it is obvious to make separable what was known in the art as combined, for use as they were described in the art (see MPEP 2143(I)), with the motivation for doing so being inherent; “if it were considered desirable for any reason (to separate)…it would be obvious” to do so, see MPEP 2144.04(V)(c). The burden is on the applicants to provide a patentable distinction between administering the composition of OPLS and antigen, of ‘688 and ‘850, for inducing immune tolerance versus administering separate injections of OPLS and antigen into the same tissue, in temporal proximity, for inducing immune tolerance. The examiner sees no patentable distinction between the two administration regimes, either in benefit or expectation for success. Therefore the examiner determines that it is obvious to modify administering the single composition, of ‘688 and ‘850, for inducing immune tolerance, into two separate injections, of the same agents, into the same tissue, in temporal proximity to one another, for the same purpose of inducing immune tolerance. Applicant’s arguments are not found persuasive; therefore, the rejection over the combination of ‘688, ‘850 and Frost et al. is maintained.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAMES R. MELCHIOR whose telephone number is (703)756-4761. The examiner can normally be reached M-F 8:00-5:00 CST.
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/JAMES RYLAND MELCHIOR/Examiner, Art Unit 1644
/DANIEL E KOLKER/Supervisory Patent Examiner, Art Unit 1644