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 .
Claim Status
Claims 2-3 and 7-10 have been cancelled and claims 1 and 5-6 have been amended, as requested in the amendment filed on 01/21/2026. Following the amendment, claims 1 and 4-6 are pending in the instant application.
Claims 1 and 4-6 are under examination in the instant office action.
Priority - Updated
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.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. It is further noted that a certified copy of an English translation of the foreign priority document was filed on 01/21/2026. As such, the claim to foreign priority has been perfected.
Claims 1 and 4-6 have an effective filing date of October 29, 2019 corresponding to CN201911038880.0.
Claim Rejections - 35 USC § 112 - Withdrawn
Claim 6 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends. Applicant has amended claim 6 to further limit claim 1 from which it depends by reciting “wherein, when X1, X2, Y1, and Y2 are all none, the bifunctional linker is coupled to nucleic acids W1, W2, T, and A”. As such, the rejection of claim 6 under 35 U.S.C. 112(d) is withdrawn.
Claim Rejections - 35 USC § 112 - Maintained
Claims 1 and 4-6 stand as rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
With regard to amended claim 1, it is noted that three formulas are defined within the claim (Formulas I-III), wherein each formula comprises differently-labeled components which are defined the same as other components of other formulas; for example, T0 of Formula I and T of Formula II are both defined as a drug component part. As such, the claim is still redundant and it is still difficult to relate the Formulas to each other. It is further noted that Formulas II and III comprise components not accounted for in Formula I, which results from the combination of Formulas II and III. Specifically Formula II recites components X1, Y1, and Z1, while Formula III recites X2, Y2, and Z2; however it becomes unclear as to how these components (when present) are incorporated into Formula III after the complementary pairing of W1 of Formula II and W2 of Formula III. Applicant is required to amend the claim for clarity such that the claim is more clearly indicates the relationship between formula components (e.g., how to arrive at Formula I based on Formulas II and III). Claims 4-5 are included in this rejection as they depend from claim 1. Thus, claims 1 and 4-5 stand as rejected under 35 U.S.C. 112(b).
With regard to amended claim 6, the wording of the claim introduces ambiguity. The claim recites that L1 and L2 each independently comprise a bifunctional linker “wherein, when X1, X2, Y1, and Y2 are all none, the bifunctional linker is coupled to nucleic acids W1, W2, T, and A”. As currently presented, the recitation of “the bifunctional linker” renders that claim ambiguous because there are two bifunctional linkers; it is unclear as to which components each linker connects to. It should be indicated which bifunctional linker (e.g., of L1 or L2) connects to which corresponding components (e.g., W1 and T/W2 and A, respectively). Thus, claim 6 is still considered to be indefinite and stands as rejected under 35 U.S.C. 112(b).
Claim Rejections - 35 USC § 103 - Withdrawn
Claims 1 and 4-6 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/205755 A1 (equivalent to US 2020/0376070 A1; previously cited on PTO-892; herein after referred to as “Chou”) in view of non-patent literature by Kuhlmann et. al. (Molecular Therapy: Nucleic Acids, 2017, 9, 284-293; NPL Citation D on 06/06/2022 IDS; herein after referred to as "Kuhlmann"), non-patent literature by Graf (Transfus. Med. Hemother., 2018, 45, 86-91; previously cited on PTO-892; herein after referred to as "Graf"), and non-patent literature by Hoefman et. al. (Antibodies, 2015, 4, 141-165; previously cited on PTO-892; herein after referred to as "Hoefman").
On Pages 7-8 of Remarks (01/21/2026), Applicant argues that the claim to foreign priority for the instant application has been perfected, and as such the Chou reference is not prior art because (i) the Chou reference was published 11/15/2018 whereas the effective filing date of the instant application is now 10/29/2019 and as such the Chou reference was published within the one-year grace period and the exception under 35 U.S.C. 102(b)(1)(A) applies wherein the Chou reference and the present invention share common inventors James Jeiwen Chou and Liqiang Pan; and (ii) the Chou reference is not prior as the exceptions under 35 U.S.C. 102(b)(2)(A) and/or 102(b)(2)(C) apply wherein the Chou reference and present application share common inventors James Jeiwen Chou and Liqiang Pan and are commonly owned by ASSEMBLY MEDICINE, LLC. As such, the rejection of claims 1 and 4-6 under 35 U.S.C. 103 over Chou, Kuhlmann, Graf, and Hoefman is withdrawn.
Claim Rejections - 35 USC § 103 - Maintained
Claims 1 and 4-6 stand as rejected under 35 U.S.C. 103 as being unpatentable over non-patent literature by Kuhlmann et. al. (Molecular Therapy: Nucleic Acids, 2017, 9, 284-293; NPL Citation D on 06/06/2022 IDS; herein after referred to as "Kuhlmann"), non-patent literature by Graf (Transfus. Med. Hemother., 2018, 45, 86-91; previously cited on PTO-892; herein after referred to as "Graf"), non-patent literature by Hoefman et. al. (Antibodies, 2015, 4, 141-165; previously cited on PTO-892; herein after referred to as "Hoefman"), and non-patent literature by Kaur et. al. (Chem. Rev., 2007, 107, 4672-4697; previously cited on PTO-892; herein after referred to as "Kaur").
On Pages 8-16 of Remarks, Applicant argues the following with regard to the rejection of claims 1 and 4-6 over Kuhlmann, Graf, Hoefman, and Kaur:
In Kuhlmann's structure, albumin serves as the half-life extension unit, and the aptamer serves as the drug moiety. The assembly structure taught by Kuhlmann is limited to (i) the drug moiety being a nucleic acid aptamer and (ii) the half-life extension unit being albumin where one half-life extension unit is connected to one drug moiety via two oligonucleotide chains. Kuhlmann does not teach or suggest any drug library having the presently claimed structure (i.e., "protein drug-nucleic acid linker-n half-life extension units" [n is an integer ≥1]), where the half-life extension unit is an anti-albumin antibody.
Kuhlmann uses recombinant human albumin (rHA) as a half-life extension carrier, which is linked to a small molecular nucleic acid drug (a FIXa aptamer) via an oligonucleotide (ODN) connector. Thus, the artisan would understand that the drug for Kuhlmann is also a low molecular weight protein. In contrast, the present claimed drug library involves the mutual linkage between a macromolecular therapeutic protein (e.g., FVIII) and an anti-albumin antibody via L-nucleic acids; therefore the instant structure is fundamentally different than that instantly claimed and a skilled artisan would recognize that replacing Kuhlmann’s small nucleic acid aptamer with macromolecular protein FVIII would present different and entirely unpredictable and challenges in terms of conjugation chemistry, steric hindrance, and activity retention, for none of which Kuhlmann provides any solution.
Graf fails to teach or suggest any drug library having the presently claimed structure and Graf does not teach or suggest how to effectively extend the half-life of FVIII.
Hoefman at best teaches that Nanobodies, as drugs, when linked to an anti-albumin Nanobody, form constructs with long circulatory half-life characteristics. However, the irrelevant Nanobody (Irr3) and the anti-albumin Nanobody (Hle2) are formed into multimers through genetic fusion or recombinant protein formats. the molecular weight of irrelevant Nanobodies is significantly lower, belonging to the category of low molecular weight proteins; a skilled artisan given the teachings of Hoefman would understand that linking low molecular weight proteins or Nanobodies to anti-albumin Nanobodies via genetic fusion may effectively enhance the half-life of these low molecular weight proteins or Nanobodies. Hoefman does not provide any suggestion regarding whether linking an anti-albumin Nanobody to a high molecular weight protein (e.g., FVIII factor of the presently claimed structure) would still effectively enhance the half-life of the high molecular weight protein and Hoefman similarly does not provide any technical suggestion on whether an anti-albumin Nanobody, when linked to a high molecular weight protein not via genetic fusion (e.g., via nucleotide sequences as in the presently claimed structure), would enhance the half-life of the connected high molecular weight protein.
The LNA/PNA technical approach taught by Kaur is not directly related to the problem of protein drug half-life extension targeted by the present application. Furthermore, Kaur provides no teaching or suggestions regarding the adaptation of nucleic acid stabilization technology for protein conjugation purposes. Thus, the technical focus of Kaur is limited to enhancing the stability and assembly capability of nucleic acid components per se. This fundamentally differs from the protein conjugation and half-life extension technical solution of the presently claimed drug library. There is no evidence on the record, or adduced by the Office, that a skilled artisan would have been directed to modify Kaur (and other cited references) to arrive at the claimed structure.
The presently claimed drug library offers unexpected results: the drug library structure significantly enhances the activity and half-life of protein drugs, as exemplified in (i) Example 5 and (ii) Figure 4 and Figure 7. In Figure 4, the half-life of the drug having the claimed structure is 22.7 hr, compared to 5.6 hr for the protein drug alone, a more than threefold increase, and in Figure 7 the activity of the
protein drug incorporating the drug library structure of the present invention is significantly enhanced wherein the average APTT activity of the protein drug alone is 60.7, whereas the activity of the protein drug with the present invention's structure unexpectedly reaches 89.68913 which is approximately 50% higher than that of the unmodified protein drug.
Applicant’s arguments have been fully considered, but are deemed not persuasive.
With regard to the cited prior art references, it is noted the teachings of the references relied upon are as follows:
Kuhlmann teaches a method of conjugating therapeutic aptamers (i.e., drug component part, e.g., FIXa blocking aptamer) to rHA (i.e., half-life extension part) for half-life extension purposes wherein the conjugation is achieved by functionalization of ODN/cODN (i.e., linker molecules attached to nucleic acid sequences with complementary paring region(s)) such that annealing (i.e., base-pairing) of said ODN with said cODN links the rHA and therapeutic aptamer. In other words, Kuhlmann teaches the general approach instantly claimed absent (i) a long-acting FVIII as a drug, (ii) an anti-albumin nanobody as a half-life extension component, and (iii) the nucleic acid sequences defined by W1 and W2 which require L-nucleic acids.
Graf teaches a need for longer acting methods to treat patients with hemophilia A or B wherein in addition to FIXa being a target of anti-thrombotic approaches, deficiencies of coagulation factors VIII (FVIII) and IX (FIX), respectively, also play a role in hemophilia pathology. Graf establishes extended half-life (EHL) products for FVIII, but indicates that advances in such products are not as impressive as those for FIX, further indicating a need for improvement in half-life extended products.
Hoefman teaches that prolonged exposure is achieved by half-life extending moieties that target endogenous albumin; half-life extended nanobodies Hle1, Irr1-Hle1 and Irr2-Hle2-Irr2 (Table 1, mono-, di- and trimeric, respectively) in mice and Irr3-Hle2 (dimeric) in monkeys showed a clear prolonged exposure compared with the non-half-life extended nanobodies Irr1 and Irr1-Irr1 (mono- and dimeric).
Kaur teaches that LNA:PNA combination is a unique example of an orthogonal programmable assembler that can serve quite well as a replacement for DNA in programmable assembly; the stability of LNA-modified oligonucleotides in biological fluids, their lack of toxicity, and their improved hybridization behavior have made them promising therapeutic tools for use in antisense and antigene applications wherein high-affinity LNAs can be readily designed as fully modified LNA, LNA/DNA chimera, LNA/ RNA chimera, or combined with other modifications such as phosphorothioate linkages or 2’-O-Me-RNA; this makes LNA compatible with different oligonucleotide chemistries and technologies.
As indicated in the previous Office Action (10/21/2025), Kuhlmann could be modified such that: (i) instead of a FIX aptamer, and half-life extended FVIII product could be utilized to further improve therapeutic options for hemophilia, for example, as suggested by Graf; (ii) functionalized (i.e., activated, linker-containing) ODNs could be utilized for conjugation of therapeutic aptamers to anti-albumin antibodies which are also expected to improve half-life, as suggested by Hoefman; and (iii) the ODNs could be modified such that they utilize LNAs and/or PNAs which are expected to better facilitate hybridization and improve stability, as suggested by Kaur. In other words: FVIII-SMCC-ODN can be conjugated to anti-albumin nanobody-SMCC-cODN wherein the ODN and cODN are complementary (at least partially) and are capable of base pairing to yield a conjugate of FVIII-SMCC-ODN//cODN-SMCC-anti-albumin nanobody. While it is acknowledged that the drug components of Kuhlmann and Hoefman are smaller than the full-length FVIII protein, there is no indication in the cited references to indicate that such a replacement is discouraged, not possible, and/or not reasonably predictable. Specifically, Graf indicates a need for improved half-life extended FVIII products, wherein it is noted that the half-life extension property as disclosed by Kuhlmann and Hoefman is endowed through interactions with albumin, whether albumin is attached to a drug itself or an anti-albumin nanobody is used to facilitate an interaction with albumin. Applicant has not provided any clear evidence indicating that using a protein (e.g., FVIII) instead of an aptamer or antibody would fundamentally change the conjugation process nor the ability of the drug to function; it is particularly noted that Graf indicates that there have been made to extend the half-life of small proteins and peptides by limiting renal elimination (proteins/peptides smaller than albumin) and/or benefiting from the FcRn salvaging pathway (proteins/peptides larger than albumin), e.g., through (i) fusion of the protein to albumin or to the Fc fragment of IgG, (ii) covalently binding to polyethylene glycol increasing its hydrodynamic radius and stability, or (iii) targeting endogenous albumin reversibly (See Page 142); thus Graf indicates larger proteins may also benefit from half-life extension technology through the exploitation of albumin and interactions thereof. Furthermore, it would be within the purview of one having ordinary skill in the art that ODNs, linkers, and combinations thereof of preferential lengths could be utilized; it is well established that linker lengths contribute to flexibility (e.g., in fusion proteins) to maintain proper spacing and functionality of linked components. Kaur is solely relied upon for the teaching that LNA:PNA combination is a unique example of an orthogonal programmable assembler and that the stability of LNA-modified oligonucleotides in biological fluids, their lack of toxicity, and their improved hybridization behavior have made them promising therapeutic tools for use in antisense and antigene applications wherein high-affinity LNAs can be readily designed as fully modified LNA, LNA/DNA chimera, LNA/RNA chimera, or combined with other modifications such as phosphorothioate linkages or 2’-O-Me-RNA; this makes LNA compatible with different oligonucleotide chemistries and technologies. Thus, Kaur suggests that the use of LNAs in oligonucleotide chemistries and technologies may be preferential and would reasonably be expected to be compatible.
With regard to the argument of unexpected results, it is noted that MPEP 716.06b recites that the evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions in appellants’ brief that the claimed polymer had an unexpectedly increased impact strength "are not entitled to the weight of conclusions accompanying the evidence, either in the specification or in a declaration."); Ex parte C, 27 USPQ2d 1492 (Bd. Pat. App. & Inter. 1992) (Applicant alleged unexpected results with regard to the claimed soybean plant, however there was no basis for judging the practical significance of data with regard to maturity date, flowering date, flower color, or height of the plant.). See also In re Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977) and In re Eli Lilly, 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) as discussed in MPEP § 716.02(c). It is noted that the data presented has no statistical analysis to support the claims of significant differences. Additionally, evidence of unexpected properties may be in the form of a direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims. See In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980) and MPEP § 716.02(d) - § 716.02(e). An affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979). “A comparison of the claimed invention with the disclosure of each cited reference to determine the number of claim limitations in common with each reference, bearing in mind the relative importance of particular limitations, will usually yield the closest single prior art reference.” In re Merchant, 575 F.2d 865, 868, 197 USPQ 785, 787 (CCPA 1978) (emphasis in original). Where the comparison is not identical with the reference disclosure, deviations therefrom should be explained, In re Finley, 174 F.2d 130, 81 USPQ 383 (CCPA 1949), and if not explained should be noted and evaluated, and if significant, explanation should be required. In re Armstrong, 280 F.2d 132, 126 USPQ 281 (CCPA 1960) (deviations from example were inconsequential). See also MPEP 716.02e. Furthermore, it is noted that the data of Example 5, Figure 4, and Figure 7 is not commensurate in scope with the claims. Notably, instant claim 1 is drawn to, generally, a “drug unit-half-life extension unit” which may comprise (i) any anti-albumin antibody and (ii) any protein drug. The data presented is drawn to a single “drug unit-half-life extension unit” comprising a specific anti-albumin nanobody and FVIII as the protein drug. It is therefore unclear if any and all anti-albumin antibodies (which could include full-length antibodies) in combination with any and all protein drugs would yield similar half-life extension results; one specific embodiment is not sufficient to establish a trend for all, or most, of the drug unit-half-life extension units of instant claim 1.
Double Patenting - Withdrawn
Claims 1 and 4-6 were rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 11,131,365 (US Patent corresponding to US 2020/0376070 A1; herein after referred to as "reference patent") in view of WO 2018/205755 A1 (equivalent to US 2020/0376070 A1; previously cited on PTO-892; herein after referred to as “Chou”) in view of non-patent literature by Kuhlmann et. al. (Molecular Therapy: Nucleic Acids, 2017, 9, 284-293; NPL Citation D on 06/06/2022 IDS; herein after referred to as "Kuhlmann"), non-patent literature by Graf (Transfus. Med. Hemother., 2018, 45, 86-91; previously cited on PTO-892; herein after referred to as "Graf"), and non-patent literature by Hoefman et. al. (Antibodies, 2015, 4, 141-165; previously cited on PTO-892; herein after referred to as "Hoefman").
Claims 1 and 4-6 were provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 and 9-12 of copending Application No. 18/254,495 (herein after referred to as "first reference application") in view of WO 2018/205755 A1 (equivalent to US 2020/0376070 A1; previously cited on PTO-892; herein after referred to as “Chou”) in view of non-patent literature by Kuhlmann et. al. (Molecular Therapy: Nucleic Acids, 2017, 9, 284-293; NPL Citation D on 06/06/2022 IDS; herein after referred to as "Kuhlmann"), non-patent literature by Graf (Transfus. Med. Hemother., 2018, 45, 86-91; previously cited on PTO-892; herein after referred to as "Graf"), and non-patent literature by Hoefman et. al. (Antibodies, 2015, 4, 141-165; previously cited on PTO-892; herein after referred to as "Hoefman").
Claims 1 and 4-6 were provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 and 5-13 of copending Application No. 18/284,836 (herein after referred to as "second reference application") in view of WO 2018/205755 A1 (equivalent to US 2020/0376070 A1; previously cited on PTO-892; herein after referred to as “Chou”) in view of non-patent literature by Kuhlmann et. al. (Molecular Therapy: Nucleic Acids, 2017, 9, 284-293; NPL Citation D on 06/06/2022 IDS; herein after referred to as "Kuhlmann"), non-patent literature by Graf (Transfus. Med. Hemother., 2018, 45, 86-91; previously cited on PTO-892; herein after referred to as "Graf"), and non-patent literature by Hoefman et. al. (Antibodies, 2015, 4, 141-165; previously cited on PTO-892; herein after referred to as "Hoefman").
As noted above, on Pages 7-8 of Remarks (01/21/2026), Applicant argues that the claim to foreign priority for the instant application has been perfected, and as such the Chou reference is not prior art because (i) the Chou reference was published 11/15/2018 whereas the effective filing date of the instant application is now 10/29/2019 and as such the Chou reference was published within the one-year grace period and the exception under 35 U.S.C. 102(b)(1)(A) applies wherein the Chou reference and the present invention share common inventors James Jeiwen Chou and Liqiang Pan; and (ii) the Chou reference is not prior as the exceptions under 35 U.S.C. 102(b)(2)(A) and/or 102(b)(2)(C) apply wherein the Chou reference and present application share common inventors James Jeiwen Chou and Liqiang Pan and are commonly owned by ASSEMBLY MEDICINE, LLC. As such, the above-listed claim rejections under nonstatutory double patenting in view of Chou, Kuhlmann, Graf, and Hoefman are withdrawn.
Double Patenting - Maintained
Claims 1 and 4-6 stand as rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 11,131,365 (US Patent corresponding to US 2020/0376070 A1; herein after referred to as "reference patent") in view of non-patent literature by Kuhlmann et. al. (Molecular Therapy: Nucleic Acids, 2017, 9, 284-293; NPL Citation D on 06/06/2022 IDS; herein after referred to as "Kuhlmann"), non-patent literature by Graf (Transfus. Med. Hemother., 2018, 45, 86-91; previously cited on PTO-892; herein after referred to as "Graf"), non-patent literature by Hoefman et. al. (Antibodies, 2015, 4, 141-165; previously cited on PTO-892; herein after referred to as "Hoefman"), and non-patent literature by Kaur et. al. (Chem. Rev., 2007, 107, 4672-4697; previously cited on PTO-892; herein after referred to as "Kaur").
Claims 1 and 4-6 stand as provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 and 9-12 of copending Application No. 18/254,495 (herein after referred to as "first reference application") in view of non-patent literature by Kuhlmann et. al. (Molecular Therapy: Nucleic Acids, 2017, 9, 284-293; NPL Citation D on 06/06/2022 IDS; herein after referred to as "Kuhlmann"), non-patent literature by Graf (Transfus. Med. Hemother., 2018, 45, 86-91; previously cited on PTO-892; herein after referred to as "Graf"), non-patent literature by Hoefman et. al. (Antibodies, 2015, 4, 141-165; previously cited on PTO-892; herein after referred to as "Hoefman"), and non-patent literature by Kaur et. al. (Chem. Rev., 2007, 107, 4672-4697; previously cited on PTO-892; herein after referred to as "Kaur").
Claims 1 and 4-6 stand as provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 and 5-13 of copending Application No. 18/284,836 (herein after referred to as "second reference application") in view of non-patent literature by Kuhlmann et. al. (Molecular Therapy: Nucleic Acids, 2017, 9, 284-293; NPL Citation D on 06/06/2022 IDS; herein after referred to as "Kuhlmann"), non-patent literature by Graf (Transfus. Med. Hemother., 2018, 45, 86-91; previously cited on PTO-892; herein after referred to as "Graf"), non-patent literature by Hoefman et. al. (Antibodies, 2015, 4, 141-165; previously cited on PTO-892; herein after referred to as "Hoefman"), and non-patent literature by Kaur et. al. (Chem. Rev., 2007, 107, 4672-4697; previously cited on PTO-892; herein after referred to as "Kaur").
One Page 17 of Remarks, Applicant argues that the reference documents (i.e., first reference patent, first reference application, and second reference application) in view of the cited prior art are patentably distinct from the instant claims. More specifically, Applicant argues that the reference patent is directed to a protein drug library comprising three or more different kinds of protein drug monomers wherein the claimed drug is an antibody and the protein drug is a multispecific antibody which addresses the problem of multi-target drugs or high-dose drugs. The first reference application is drawn to a multivalent protein drug or vaccine with the purpose of increasing the number of drug or vaccine entities by forming oligomeric or multivalent forms, therefor augmenting active components and extending half-life without including any components specifically intended to extend half-life. The second reference application is drawn to an antibody-drug conjugate wherein the purpose is to enhance the targeting precision of the therapeutic payload. Applicant argues that, in contrast, the instant claims are drawn to a protein drug library comprising a protein drug and an anti-albumin antibody wherein the anti-albumin antibody is intended solely for prolonging the half-life of the protein drug and further wherein an exemplary protein drug is long-acting FVIII; none of the cited reference patent and/or reference applications teach or suggest the instantly claimed protein drug library and, as discussed in the 103 section above, (i) the cited prior art references are also distinguishable, (ii) a skilled artisan would not have been motivated to modify the reference patent and/or reference applications to arrive at the instantly claimed protein drug library with a reasonable expectation of success, and (iii) the instantly claimed drug library offers unexpected results.
Applicant’s arguments have been fully considered, but are deemed not persuasive.
As noted in the previous Office Action:
With regard to the reference patent, it would have been obvious to one of ordinary skill in the art that the approach/drug library of the reference patent could be modified such that instead of a multimeric antibody, the protein drug components could comprise an antibody and a non-antibody therapeutic agent, as suggested by the reference patent and Kuhlmann, wherein: (i) instead of a FIX aptamer suggested by Kuhlman, a half-life extended FVIII product could be utilized to further improve therapeutic options for hemophilia, for example, as suggested by Graf; (ii) functionalized (i.e., activated, linker-containing) ODNs could be utilized for conjugation of therapeutic aptamers to anti-albumin antibodies which are also expected to improve half-life, as suggested by Hoefman; and (iii) the ODNs could be modified such that they utilize LNAs and/or PNAs which are expected to better facilitate hybridization and improve stability, as suggested by Kaur. In other words: FVIII-SMCC-ODN can be conjugated to anti-albumin nanobody-SMCC-cODN wherein the ODN and cODN are complementary (at least partially) and are capable of base pairing to yield a conjugate of FVIII-SMCC-ODN//cODN-SMCC-anti-albumin nanobody; therefor the combination of references meets the limitations of claims 1 and 4-6. Combining prior art elements according to known methods would be expected to yield predictable results wherein the resultant conjugate(s) comprising a drug component (e.g., FVIII) linked to at least one half-life extension unit (anti-albumin nanobody) via a linker (e.g., SMCC, bifunctional reacting with the free thiol of rHA and the terminal amine of a nucleic acid sequence) and nucleic acid sequence (e.g., LNA/PNAs which are complementary and anneal/base pair) would reasonably be expected to have an increased the half-life of the drug component/drug library.
With regard to the first reference application, it would have been obvious to one of ordinary skill in the art that the multimeric complex/nucleic acid sequence library of the first reference application could be modified such that instead of a generic polypeptide-based multimeric complex, the polypeptide components could more specifically be an antibody and a non-antibody therapeutic agent, as suggested by Kuhlmann, wherein: (i) instead of a FIX aptamer suggested by Kuhlman, a half-life extended FVIII product could be utilized to further improve therapeutic options for hemophilia, for example, as suggested by Graf; (ii) functionalized (i.e., activated, linker-containing) ODNs could be utilized for conjugation of therapeutic aptamers to anti-albumin antibodies which are also expected to improve half-life, as suggested by Hoefman; and (iii) the ODNs could be modified such that they utilize LNAs and/or PNAs which are expected to better facilitate hybridization and improve stability, as suggested by Kaur. In other words: FVIII-SMCC-ODN can be conjugated to anti-albumin nanobody-SMCC-cODN wherein the ODN and cODN are complementary (at least partially) and are capable of base pairing to yield a conjugate of FVIII-SMCC-ODN//cODN-SMCC-anti-albumin nanobody; therefor the combination of references meets the limitations of claims 1 and 4-6. Combining prior art elements according to known methods would be expected to yield predictable results wherein the resultant conjugate(s) comprising a drug component (e.g., FVIII) linked to at least one half-life extension unit (anti-albumin nanobody) via a linker (e.g., SMCC, bifunctional reacting with the antibody and the terminal amine of a nucleic acid sequence) and nucleic acid sequence (e.g., LNA/PNAs which are complementary and anneal/base pair) would reasonably be expected to have an increased the half-life of the drug component wherein the multimeric complexes could make up a drug library comprising various nucleic acid sequences for base-pairing based conjugation and various long-acting FVIII products, suggested by the first reference application, Kuhlmann, and/or Graf.
With regard to the second reference application, it would have been obvious to one of ordinary skill in the art that the antibody-drug conjugate of the second reference application could be modified such that instead of a generic antibody/drug combination, the components could more specifically be targeted to hemophilia, as suggested by the conjugate of Kuhlmann, wherein: (i) instead of a FIX aptamer suggested by Kuhlman, a half-life extended FVIII product could be utilized to further improve therapeutic options for hemophilia, for example, as suggested by Graf; (ii) functionalized (i.e., activated, linker-containing) ODNs could be utilized for conjugation of therapeutic aptamers to anti-albumin antibodies which are also expected to improve half-life, as suggested by Hoefman; and (iii) the ODNs could be modified such that they utilize LNAs and/or PNAs which are expected to better facilitate hybridization and improve stability, as suggested by Kaur. In other words: FVIII-SMCC-ODN can be conjugated to anti-albumin nanobody-SMCC-cODN wherein the ODN and cODN are complementary (at least partially) and are capable of base pairing to yield a conjugate of FVIII-SMCC-ODN//cODN-SMCC-anti-albumin nanobody; therefor the combination of references meets the limitations of claims 1 and 4-6. Combining prior art elements according to known methods would be expected to yield predictable results wherein the resultant conjugate(s) comprising a drug component (e.g., FVIII) linked to at least one half-life extension unit (anti-albumin nanobody) via a linker (e.g., SMCC, bifunctional reacting with the antibody and the terminal amine of a nucleic acid sequence) and nucleic acid sequence (e.g., LNA/PNAs which are complementary and anneal/base pair) would reasonably be expected to have an increased the half-life of the drug component wherein the antibody-drug conjugates could make up a drug library comprising various nucleic acid sequences for base-pairing based conjugation and various long-acting FVIII products, as suggested by the second reference application, Kuhlmann, and/or Graf.
Thus, the prior art references provide a motivation to modify wherein, as discussed above, Graf specifically indicates the need to half-life extended drugs (e.g., FVIII specifically) wherein Kuhlmann and Hoefman teach half-life may extension is endowed through interactions with albumin, whether albumin is attached to a drug itself or an anti-albumin nanobody is used to facilitate an interaction with albumin. Furthermore, Kuhlmann and/or the reference patent/applications teach the general complementary nucleic acid conjugation technology/approach instantly claimed, and Kaur suggests that the use of LNAs in oligonucleotide chemistries and technologies may be preferential and would reasonably be expected to be compatible. It is noted that the arguments of unexpected results has also been addressed above, wherein the data presented has no statistical analysis to support the claims of significant differences and the data of Example 5, Figure 4, and Figure 7 is not commensurate in scope with the claims. Notably, instant claim 1 is drawn to, generally, a “drug unit-half-life extension unit” which may comprise (i) any anti-albumin antibody and (ii) any protein drug. The data presented is drawn to a single “drug unit-half-life extension unit” comprising a specific anti-albumin nanobody and FVIII as the protein drug. It is therefore unclear if any and all anti-albumin antibodies (which could include full-length antibodies) in combination with any and all protein drugs would yield similar half-life extension results; one specific embodiment is not sufficient to establish a trend for all, or most, of the drug unit-half-life extension units of instant claim 1.
As such, the above-listed claim rejections under nonstatutory double patenting over the reference patent, first reference application, and second reference application in view of Kuhlmann, Graf, Hoefman, and Kaur are maintained.
Conclusion
Claims 1 and 4-6 are pending. Claims 1 and 4-6 are rejected. No claims are allowed.
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/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642