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 amendment, filed on 10/11/2023, is acknowledged.
Claims 5, 7, 10, 11, 16-18, 23, 24, 27-30, 34, 35, 37-51, and 54-57 are cancelled.
Claims 1-4, 6, 8, 9, 12-15, 19-22, 25, 26, 31-33, 36, 52, and 53 are currently pending.
Claims 1 and 2 are independent claims.
Election/Restrictions
Applicant’s election of Group I, claims 1-4, 6, 8, 9, 12-15, 19-22, 25, 26, 31-33, 36, and 52; and the Species of: i) SEQ ID NO: 110; ii) the conjugate formula of claim 14; iii) the D-Ala-Pro linker; iv) the first SRS structure in claim 20 wherein R2 is H, R3 is H, R4 is a branched lower alkoxy, X1 is O, and X2 is O; and v) Val-boroPro therapeutic moiety in the reply filed on 2/2/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
The elected species of conjugate in claim 14 is as follows and is annotated to show the different moieties found in the conjugate:
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494
1061
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The structure of this elected species of conjugate does not have a self-immolative linker between the SRS and the TM, and therefore claims 12 and 13 do not read on the elected species of conjugate. The elected species of conjugate also does not comprise a receptor binding motif (RBM), and therefore claim 36 also does not read on the elected species.
Val-boroPro/talabostat is a iDASH inhibitor chemotherapeutic moiety (disclosed in the specification on pg. 11), and is acutely cytotoxic to macrophages (Example 4). Claim 26 does not read on this elected species of therapeutic moiety.
Additionally, the elected species of SRS is as follows (Applicant remarks filed 2/02/2026):
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174
648
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However, the elected conjugate of claim 14 contains a SRS wherein X1 and X2 are O, R2 is H, R3 is a C1 alkyl, and R4 is a 4-carbon non-branched alkane (i.e., proline). To ensure clarity of record as to the elected species of conjugate and SRS, the search of the species of SRS in claim 20 has been extended to cover the nonelected species as well.
Claims 12, 13, 26, 36, and 53 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions and/or.
Claims 1-4, 6, 8, 9, 14, 15, 19-22, 25, 31-33, and 52 are under examination as reading on a therapeutic conjugate comprising a therapeutic moiety linked to a half-life extension moiety via a FAPα cleavable linker.
Priority
Applicant’s claim for the benefit of a prior-filed US 63/108,020, filed October 30, 2020 and US 63/197,926, filed June 7, 2021, is acknowledged.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 7/27/2023 and 2/02/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner in their entireties.
Claim Objections
Claim 19 currently recites “D-Ala-Pro”. It is recommended to amend the claim to recite “(d)-Ala-Pro” to clarify that the sequence represents the (d)-Ala stereoisomer followed by a Pro residue and not an Asp-Ala-Pro peptide sequence.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-4, 6, 8, 9, 14, 15, 19-22, 25, 31-33, and 52 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventors, at the time the application was filed, had possession of the claimed invention.
Claims 1-4, 6, 8, 9, 15, 20-22, 25, 31-33, and 52 encompass therapeutic conjugates comprising linkers with a partial structure at best and the function of “FAPα-cleavable linker”.
Additionally, claims 1-4, 6, 8, 9, 14, 15, 19-22, 25, 31-33, and 52 encompass therapeutic conjugates comprising moieties with a partial structure at best and the functions of “half-life extension moiety” and “serum half-life of the therapeutic conjugate in vivo is at least 48 hours” (claims 1, 3, 4, 6, 8, 9, 14, 15, 19-22, 25, 31-33, and 52), or “half-life extension moiety” and “serum half-life of the therapeutic conjugate in vivo is extended by more than 2-fold relative to circulating serum half-life of a free therapeutic moiety” (claim 2).
However, the specification fails to provide adequate written description support for a genus of linkers with a partial structure at best having the desired functional properties required to practice the claimed function “FAPα-cleavable linker” (claims 1-4, 6, 8, 9, 15, 20-22, 25, 31-33, and 52); and the specification fails to provide adequate written description support for a genus of moieties with a partial structure at best and the function of “half-life extension moiety” (claims 1-4, 6, 8, 9, 14, 15, 19-22, 25, 31-33, and 52).
The claims are not supported by a description that satisfies 35 U.S.C. § 112(a) or 35 U.S.C. § 112, first paragraph. "[T]he test for sufficiency [of the written description] is whether the disclosure of the application relied upon reasonably conveys to those skilled in the art that the inventor had possession of the claimed subject matter as of the filing date." Ariad Phanns., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en bane).
A "sufficient description of a genus ... requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can 'visualize or recognize' the members of the genus." Id. at 1350. "[A]n adequate written description requires a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials." Id.
"[F]unctional claim language can meet the written description requirement when the art has established a correlation between structure and function." Id. "But merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing that one has invented a genus and not just a species." Id.
"A sufficient description of a genus ... requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can "visualize or recognize" the members of the genus" (AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69) (emphasis added).
Regarding the claimed genera of linkers with a partial structure at best having the desired functional properties required to practice the claimed function “FAPα-cleavable linker” (claims 1-4, 6, 8, 9, 15, 20-22, 25, 31-33, and 52), the specification discloses specific examples of FAPα cleavable linkers that are all oligopeptide substrate recognition sequences of varying length, all of which end in either a proline or a Pro-Ala-Xaa tripeptide (pg. 45, claim 19).
Regarding the claimed genera of moieties with a partial structure at best and the function of “half-life extension moiety” (claims 1-4, 6, 8, 9, 14, 15, 19-22, 25, 31-33, and 52), the instant specification discloses that serum proteins such as fibronectin, transferrin, and HSA, or an antibody Fc domains can function as half-life extension moieties (pg. 16-18). The instant specification further discloses that half-life extension moieties can also be moieties that specifically bind to serum proteins such as HSA. The instant specification discloses sequences of affimers that specifically bind to HSA and can function as half-life extension moieties (SEQ ID NO: 110-132, Tables 1-3), however does not disclose any other structures (small molecules, aptamers, etc.) that bind to serum proteins and has the function of “half-life extension moiety”.
With respect to representative number of species, see AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc. (Fed. Cir. 2014). Also, see MPEP 2163 Il(A)(3)(a))(ii):
A representative number of species means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See Abb Vie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus.").
Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are "representative of the full variety or scope of the genus," or by the establishment of "a reasonable structure-function correlation." Such correlations may be established "by the inventor as described in the specification," or they may be "known in the art at the time of the filing date." See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014) (Holding that claims to all human antibodies that bind IL-12 with a particular binding affinity rate constant (i.e., koff) were not adequately supported by a specification describing only a single type of human antibody having the claimed features because the disclosed antibody was not representative of other types of antibodies in the claimed genus, as demonstrated by the fact that other disclosed antibodies had different types of heavy and light chains, and shared only a 50% sequence similarity in their variable regions with the disclosed antibodies.).
In the instant case, regarding the claimed genera of linkers with a partial structure at best having the desired functional properties required to practice the claimed function “FAPα-cleavable linker” (claims 1-4, 6, 8, 9, 15, 20-22, 25, 31-33, and 52), the instant specification discloses peptide sequences of known oligopeptides that are cleaved by the FAPα serine protease, all of which have a proline in the substrate recognition sequence. No other representative species are disclosed, including linkers with SRS structures other than proline, that have the function of “FAPα-cleavable linker”. These limited number of sequences do does not sufficiently represent the broadly claimed genera of linkers with a partial structure at best and the recited function of “FAPα-cleavable linker”.
Regarding the claimed genera of moieties with a partial structure at best and the function of “half-life extension moiety” (claims 1-4, 6, 8, 9, 14, 15, 19-22, 25, 31-33, and 52), the instant specification discloses a subgenus of moieties that bind to serum proteins, anti-HSA affimers, however this subgenus does not sufficiently represent the broadly claimed genus of moieties with a partial structure at best and the function of “half-life extension moiety” recited in claims 1-4, 6, 8, 14, 15, 19-22, 25, 31-33, and 52.
Additionally, instant claims 8 and 9 recites a more limited subgenus of affimers with no structure (claim 8) or that are at least 70%, 80%, or 90% identical to the instantly elected SEQ ID NO: 110 (claim 9) that have the function of “half-life extension moiety” by specifically binding to HSA. Regarding claim 9, the total number of variants of a polypeptide having a specific number of amino acid substitutions can be calculated from the formula:
N
!
*
19
A
N
-
A
!
A
!
Where N is the length in amino acids of the reference polypeptide and A is the number of allowed substitutions. For a polypeptide that is 112 residues in length with 11 allowed substitutions (10% variation within SEQ ID NO: 110 allows for 11 substitutions), there would be
112
!
*
19
(
11
)
112
-
11
!
11
!
Which is approximately 1.74x1032 variants, including variants that have amino acid substitutions in the loop regions that are critical for specific antigen binding. The limited number of affimer examples disclosed does not sufficiently represent this diverse genus of anti-HSA affimers.
Moreover, there is insufficient written description of the required kind of structure-identifying information about the corresponding makeup of the claimed FAP cleavable linkers and half-life extension moieties antigen binding constructs to demonstrate possession. Also, see Amgen Inc. v. Sanofi, Aventisub LLC, No. 2017-1480 (Fed. Cir. 2017). The Court reiterated that adequate written description must “contain enough information about the actual makeup of the claimed products . . . .” The Court simultaneously suggested that the “newly characterized antigen” test “flouts” section 112 because it “allows patentees to claim antibodies by describing something that is not the invention, i.e., the antigen.” The Court concluded that for written description of an antibody to be adequate when presented with “functional” terminology, there must be an established correlation in the art between structure and function.
Given the broadly claimed classes of FAP cleavable linkers and half-life extension moieties, and in the absence of sufficient disclosure of relevant identifying characteristics for the broadly claimed classes of FAP cleavable linkers and half-life extension moieties, the patentee must establish “a reasonable structure-function correlation” either within the specification or by reference to the knowledge of one skilled in the art with functional claims. AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc. (Fed. Cir. 2014), MPEP 2163.
Regarding the claimed genera of linkers with a partial structure at best having the desired functional properties required to practice the claimed function “FAPα-cleavable linker” (claims 1-4, 6, 8, 9, 15, 20-22, 25, 31-33, and 52), the instant specification discloses consensus oligopeptide sequences that are cleaved by FAPα, which are claimed in instant claim 19. One of the cleavable linkers, (d)-Ala-Pro, is recited in claim 14 as well.
Additionally, FAPα cleavable consensus peptide sequences have been discovered in the prior art. Aggarwal et al. (Biochemistry. 2008 Jan 22;47(3):1076-86. doi: 10.1021/bi701921b. Epub 2007 Dec 21) teaches (Introduction): “…we present results using liquid chromatography/tandem mass spectrometry (LC/MS/MS) to generate a complete map of FAP cleavage sites within recombinant forms of human collagen I derived gelatin. We have synthesized selected peptides on the basis of these cleavage maps and analyzed them for hydrolysis by FAP to identify peptides that could be used to target cytotoxins to FAP-expressing tumor tissue.” Aggarwal et al. identified the following sequences that were found to be FAPα cleavable peptide sequences: (d)Ala-Pro (pg. 4, final ¶), PPGP, (D/E)-(R/K)-G-(E/D)-(T/S)-G-P, and DRGETP (Abstract). Additionally, Ji et al. (Angew Chem Int Ed Engl. 2016 Jan 18;55(3):1050-5. doi: 10.1002/anie.201506262. Epub 2015 Aug 17) identified another FAPα cleavable peptide sequence, which is GPAX, where X is any amino acid sequence (pg. 1050). Other than these consensus sequences, no other structure-function relationship between a peptide sequence and the function of “FAPα-cleavable” have been found, especially ones where the proline has been modified to an alkoxy (i.e., the structures recited in claim 20).
Regarding the claimed genera of moieties with a partial structure at best and the function of “half-life extension moiety” (claims 1-4, 6, 8, 9, 14, 15, 19-22, 25, 31-33, and 52), the specification lists multiple affimer sequences that have the function of specifically binding to HSA that have the function of “half-life extension moiety” (Tables 1-3).
No other serum protein binding moieties, such as antibodies, small molecules, aptamers, etc. have been described, and no structure-function relationship between these broad genera of serum protein binding moieties and the function of “half-life extension moiety”.
For these broadly recited genera of serum protein binding moieties with no recited structure (claims 1-4, 6, 14, 15, 19-22, 25, 31-33, and 52), the specification at best describes a plan for making half-life extension moieties that bind to serum proteins, and then identifying those that satisfy the claim limitations, but a mere “wish or plan” for obtaining claimed invention is not sufficient. Centocor Ortho Biotech Inc. v. Abbott Laboratories, 97 USPQ2d 1870 (Fed. Cir. 2011).
Additionally, the disclosure does not provide information sufficient to establish that a skilled artisan would understand how to identify the species of binding moieties (antibodies, scFvs, sdAbs, aptamers, etc.) capable of binding to any target (claims 1, 2, 14, 15, 19-22, 25, 31-33, and 52), any “serum protein” (claim 3), or the serum proteins recited in claims 4 and 6 to lead to the function of “half-life extension moiety” that the claims require. Without more in the disclosure, such as characteristics of exemplary binding moieties other than affimers that allow them to bind to particular targets, the mere fact that binding moieties that can bind to proteins to act as a “half-life extension moiety” in general bind does not demonstrate possession of the broad genera of binding molecules encompassed by the claims. Furthermore, the disclosure fails to disclose a method to distinguish those binding molecules that are incapable of binding the recited targets from ones that do.
Regarding the broad genera of biocompatible polymers with the function of “half-life extension moiety”, which includes the recited function “serum half-life…in vivo is at least 48 hours” (claim 3; see discussion of claim scope supra), the instant specification discloses broad classes of polymers that can be biocompatible (pg. 41-42), however does not distinguish which specific structures have the recited half-life extension functions recited the claims, and does not disclose any relationship between a polymer’s structure and the function of “half-life extension moiety”. The prior art also teaches that there is unpredictability between a polymer’s structure and the function of “half-life extension moiety”. Podust et al. (J Control Release. 2016 Oct 28;240:52-66. doi: 10.1016/j.jconrel.2015.10.038. Epub 2015 Oct 30), teaches that different XTEN structures can extent the half-life of therapeutics, however the half-life ranges from under 2.5 hours to over 72 based on the specific XTEN structure (Table 2). Additionally, Reichard et al. (Pharm Res. 2016 Dec;33(12):2954-2966. doi: 10.1007/s11095-016-2017-y. Epub 2016 Sep 12) teaches that PEGylation of can increase the serum half-life of a therapeutic to 25 hours (Table II), however this does not fall within the scope of the instant claims, as the function of “half-life extension moiety” recited in claim 1 includes a serum half-life greater than 48 hours. Neither the instant specification nor the prior art discloses sufficient structure identifying characteristics to identify which “biocompatible polymer” species in the broadly recited genus have the recited function of “half-life extension moiety”, or how to distinguish between structures with this function and those without.
Additionally, regarding the broadly claimed genera anti-HSA affimers with a partial structure at best (claim 8), and with significant variation in the critical loop sequences responsible for specific binding (claim 9), the specification discloses specific anti-HSA affimer structures, defined by their amino acid sequences, that have the function of “half-life extension moiety”. Neither the instant specification nor the prior art provide a structure-function relationship between an affimer’s amino acid sequence and the function of specifically binding HSA to be a “half-life extension moiety”.
Furthermore, Stadler et al. (Protein Eng Des Sel. 2011 Sep;24(9):751-63. doi: 10.1093/protein/gzr019. Epub 2011 May 25) teaches that affimers based on the stefin A peptide scaffold can have their loop regions vary in amino acid sequence to generate combinatorial libraries that can be screened for specific binding to different targets, much like antibodies (Introduction): “[a] new variant scaffold, SQT (Stefin A Quadruple Mutant—Tracy), is able to present a range of peptides and shows thermostability similar to that of the parental Stefin A protein. Peptide aptamers, which we now call Scannins, presenting ‘epitope tag’ peptides in the N-terminus, loop 1 and/or loop 2 of SQT… Scannins are likely to be broadly useful in presenting a wide range of peptides for interaction using three independent sites, with protein binding affinities and stabilities that can be tuned to the experimental setting.”
The prior art teaches that affimers based on stefin A have a constant scaffold with varied N-terminal, loop 1, and loop 2 regions that determine specific binding to different targets. Tiede et al. (Elife. 2017 Jun 27;6:e24903. doi: 10.7554/eLife.24903) demonstrates these loop regions (top of figure below) vary in sequence, and therefore size and 3-dimensional structure, to determine specific binding (Fig. 1):
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Neither the instant specification nor the prior art disclose a relationship between the amino acid sequences of an affimer’s variable loop regions and HSA binding that leads to the function of “half-life extension moiety”. The only structure function relationship is to list specific affimer sequences that have this function.
Additionally, the current state of the art teaches that there is unpredictability in determining which anti-HSA affimer structures that are defined by their amino acid sequences would have the recited function of “half-life extension moiety”. Gomes et al. (avacta.com/wp-content/uploads/2019/10/POS018_Serum_Albumin.pdf; first available 6/02/2023) teaches that five different anti-HSA affimers extend serum half-life in the range of 24.3-38.2 hours (Table 2), and therefore none of these different anti-HSA affimer species would fall within the scope of the claims, as claim 1 also recites “serum half-life…in vivo is at least 48 hours”. Neither the prior art nor the instant specification discloses how to distinguish between different defined affimer structures and the recited function of “half-life extension moiety”. Undue experimentation would be required by one with ordinary skill in the art to determine this, as one would need to test each individual affimer structure (defined by their amino acid sequence) to determine if: 1) the affimer extends the serum half-life of a therapeutic; and 2) if the half-life is greater than 48 hours, as not all anti-HSA affimers would extend serum half-life by this amount.
Possession is not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features. See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895. Sufficient description to show possession of such a genus may be achieved by means of a recitation of a representative number of anti-TMPRSS6 antibodies or antigen binding fragments thereof falling within the scope of the genus or of a recitation of structural features common to members of the genus, which features constitute a substantial portion of the genus. See Eli Lilly, 119F.3d at 1568, 43 USPQ2d at 1406.
Claims 1-4, 6, 8, 9, 14, 15, 19-22, 25, 31-33, and 52 do not meet the requirements of 35 U.S.C. 112(a) for written description.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the written description inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.). Consequently, Applicant was not in possession of the instant claimed invention. See University of California v. Eli Lilly and Co. 43 USPQ2d 1398.
Applicant is invited to point to clear support or specific examples of the claimed invention in the specification as-filed.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 9 and 21 are 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.
Regarding claim 9, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 9 recites the broad sequence identity “at least 70%”, followed by the narrower ranges “at least 80%” and “at least 90%”.
Claim 21 recites the limitations "third amino position” and “N-terminal to (d)-Ala”. There is insufficient antecedent basis for this limitation in the claim. Claim 1, which claim 21 is dependent from, does not recite a first or a second amino acid position, nor does it recite (d)-Ala as one of these amino acids.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-4, 6, 15, 19-22, 25, and 52 are rejected under 35 U.S.C. 103 as being unpatentable over Bachovchin et al. (U.S. Patent 9,956,297) in view of Müller et al. (MAbs. 2012 Nov-Dec;4(6):673-85. doi: 10.4161/mabs.22242).
Claims 1 and 2 claim a therapeutic agent comprising a therapeutic moiety linked to a half-life extending moiety via a FAPα cleavable domain, wherein the therapeutic does not comprise a cell binding moiety that binds to a cell surface protein of a cell with a Kd of 1x10-6 M or less, and wherein the serum half-life of the therapeutic is at least 48 hours (claim 1) or is at least 2-fold longer that the therapeutic without the half-life extending moiety (claim 2).
Bachovchin et al. teaches FAP-activated proteasome inhibitor therapeutic conjugates comprising a Ser-(d)Ala-Pro FAPα cleavable linker bound to a proteasome inhibitor (Col. 22, also see below):
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323
720
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Bachovchin et al. teaches methods of treating cancer comprising administration of these therapeutic compounds (claims 1 and 2).
Bachovchin et al. does not teach the conjugates linked to half-life extension moiety.
Müller et al., in the same field of endeavor, teaches that removal of the Fc domain or other half-life extending moieties in a therapeutic may pose issues when used to treat disease (Introduction): “[t]he challenge being that the loss of the Fc domain and the reduction in size results in more rapid clearance of the molecules, which may be advantageous for diagnostic imaging, but is far from optimal for the treatment or management of chronic disease…”
Müller et al. teaches anti-HSA IgNAR binding domains that can be used to extend the serum half-life of therapeutics that it is conjugated to (Introduction): “…we isolated a high affinity anti-HSA VNAR binding domain through immunization of a novel shark species… this is the first report of the use of this class of binding domain to affect in vivo retention by increasing the sera half-life of a fused domain…” Müller et al. further teaches potential benefits of increasing the serum half-life of therapeutics (Introduction): “[t]ailoring the half-life of therapeutic drugs would negate the requirement for multiple administrations, hence minimizing accumulative damage to the patient, increasing patient compliance and reducing the overall dosing regimen. Importantly, it would also open the opportunity to develop short-lived molecules, previously deemed unsuitable for drug development, into effective therapeutic agents.”
Müller et al. teaches that fusion of an anti-HSA IgNAR to another VNAR domain that does not bind a target increases that serum half-life (pg. 675): “[t]o determine the efficacy of the anti-HSA VNAR domains to increase the serum half-life of another unrelated VNAR domain, fusions consisting of both N-terminally and C-terminally linked HSA-binding E06 to a random naïve VNAR domain known as 2V (sequence shown in Fig. 3B) were constructed…”. The anti-HSA VNAR fusion constructs increased serum half-life by over 100-fold in mice when compared to the conjugate without the anti-HSA VNAR, and the serum half-life was over 150 hours in nonhuman primates (Table 2).
Müller et al. further teaches (Discussion): “[t]he lead clone isolated exhibited the ability to improve the PK parameters of a fused tandem VNAR domain exhibiting serum half-life values equating to that of albumin itself. This study provides the potential of these single binding domains to… act as tools to improve the PK properties of other biologic proteins.”
It would have been obvious to one of ordinary skill of the art, before the effective filing date of the instant application, to have modified the conjugate taught by Bachovchin et al. in view of Müller et al. to fuse the anti-HSA VNAR of Müller et al. to the FAPα activatable protease inhibitor of Bachovchin et al. (i.e., the limitations of instant claims 1 and 2) with a reasonable expectation of success, as Müller et al. teaches a method of conjugating the anti-HSA VNAR to other peptides, and the therapeutic of Bachovchin et al. has a peptide FAPα cleavable peptide moiety that can be fused to the anti-HSA VNAR (thus, the conjugate would have the anti-HSA VNAR conjugated to the protease inhibitor via the FAPα cleavage site). One would have been motivated to make this change to increase the half-life of the FAPα activatable protease inhibitor of Bachovchin et al., which would reduce the frequency of administration and improve patient compliance and quality of life.
The combined references do not teach the conjugate comprising a cell binding moiety.
Regarding claims 3, 4, and 6, the anti-HSA VNAR of Müller et al. is a shark antibody molecule that binds to HSA, meeting the claim limitations.
Regarding claims 15, 19-21, the FAPα cleavage site taught by Bachovchin et al. is Ser-(d)Ala-Pro, meeting the claim limitations. (d)Ala-Pro is represented by the following structure recited in claim 20:
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Wherein R3 is a 1-carbon lower alkyl group.
Regarding claims 22, and 25, Bachovchin et al. teaches that the proteasome inhibitors are acutely cytotoxic once activated (Col. 40, lines 44-46): “…pro-drug version of a bortezomib-like cytotoxic agent designed to more selectively target the proteasome in solid tumors…”, meeting the claim limitations.
Regarding claim 52, Bachovchin et al. teaches pharmaceutical compositions comprising the therapeutic and an acceptable excipient (Col. 23, lines 1-4).
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 31-33 are rejected under 35 U.S.C. 103 as being unpatentable over Bachovchin et al. (supra) and Müller et al. (supra), as applied to claims 1-4, 6, 15, 19-22, 25, and 52 above, and further in view of Walsh et al. (PLoS One. 2013;8(3):e58860. doi: 10.1371/journal.pone.0058860 Epub 2013 Mar 12) and Poplawski et al. (J Med Chem. 2011 Apr 14;54(7):2022-8. doi: 10.1021/jm100972f. Epub 2011 Mar 9), as evidenced by MCE (Talabostat safety data sheet; file.medchemexpress.com/batch_PDF/HY-13233A/Talabostat-mesylate-SDS-MedChemExpress.pdf)
The combined teachings of Bachovchin et al. and Müller et al. are discussed supra. The combined references do not teach the therapeutic moiety as Val-boroPro, which is an iDASH inhibitor with acute toxicity (i.e., the limitations of claims 31-33).
Walsh et al., in the same field of endeavor, teaches Val-boroPro can enhance immune T-cell responses to reduce tumor growth in multiple mouse tumor models (Abstract): “…Val-boroPro has antitumor activity and a novel mechanism of action that involves more robust DC trafficking with earlier priming of T cells…” Walsh et al. teaches that Val-boroPro can lead to tumor regression when administered to solid tumors (Fig. 1 and 2). Walsh et al. further teaches (pg. 12): “…our results demonstrate that the boronic dipeptide Val-boroPro induces T cell-mediated tumor rejection via a novel mechanism that involves accelerated T cell priming and enhanced DC trafficking…Val-boroPro represents a novel class of agent for boosting endogenous antitumor immune responses…”
Poplawski et al., in the same field of endeavor, teaches that Val-boroPro can be incorporated into an activatable form that is cleaved by proteases, including the (d)Ala-Pro substrate recognition sequence (Compound 5):
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Poplawski et al. teaches that Val-boroPro is a FAP inhibitor, and FAP inhibition has anticancer effects (Introduction): “…1 is a relatively nonspecific inhibitor of serine hydrolyses that cleave after proline, inhibiting other members of this group, which include FAP… FAP inhibition has been reported to yield anticancer effects…”
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the instant application, to have modified the conjugate taught by the combined references of Bachovchin et al. and Müller et al. in view of Walsh et al. and Poplawski et al. to have exchange the protease inhibitor therapeutic moiety with Val-boroPro (i.e., the limitations of instant claims 32 and 33) with a reasonable expectation of success, as Poplawski et al. teaches that Val-boroPro can be conjugated to cleavable linkers such as (d)Ala-Pro. One would have been motivated to make this change to make a FAPα-activatable version of the FAPα inhibitor Val-boroPro to treat cancers such as solid tumors.
Regarding instant claim 31, MCE is provided as an evidentiary reference to demonstrate that talabostat/Val-boroPro has acute oral toxicity (Section 2.1), meeting the claim limitations.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-4, 6, 15, 19-22, 25, and 52 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-27 of U.S. Patent No. 9,597,410 (herein Pat ‘410) in view of Müller et al. (MAbs. 2012 Nov-Dec;4(6):673-85. doi: 10.4161/mabs.22242, supra), as evidenced by Bachovchin et al. (U.S. Patent 9,956,297, supra).
Pat ‘410 claims FAP-activated proteasome inhibitors comprising a Ser-(d)Ala-Pro FAPα cleavable linker bound to a proteasome inhibitor (claim 3):
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Pat ‘410 additionally teaches methods of treating cancer comprising administration of the therapeutic (claim 22).
Bachovchin et al. is provided as an evidentiary reference to demonstrate that the proteasome inhibitors are acutely cytotoxic once activated (Col. 40, lines 44-46): “…pro-drug version of a bortezomib-like cytotoxic agent designed to more selectively target the proteasome in solid tumors…”, which are the limitations of instant claims 22 and 25.
Pat ‘410 does not teach the conjugates linked to half-life extension moiety.
Müller et al., in the same field of endeavor, teaches that removal of the Fc domain or other half-life extending moieties in a therapeutic may pose issues when used to treat disease (Introduction): “[t]he challenge being that the loss of the Fc domain and the reduction in size results in more rapid clearance of the molecules, which may be advantageous for diagnostic imaging, but is far from optimal for the treatment or management of chronic disease…”
Müller et al. teaches anti-HSA IgNAR binding domains that can be used to extend the serum half-life of therapeutics that it is conjugated to (Introduction): “…we isolated a high affinity anti-HSA VNAR binding domain through immunization of a novel shark species… this is the first report of the use of this class of binding domain to affect in vivo retention by increasing the sera half-life of a fused domain…” Müller et al. further teaches potential benefits of increasing the serum half-life of therapeutics (Introduction): “[t]ailoring the half-life of therapeutic drugs would negate the requirement for multiple administrations, hence minimizing accumulative damage to the patient, increasing patient compliance and reducing the overall dosing regimen. Importantly, it would also open the opportunity to develop short-lived molecules, previously deemed unsuitable for drug development, into effective therapeutic agents.”
Müller et al. teaches that fusion of an anti-HSA IgNAR to another VNAR domain that does not bind a target increases that serum half-life (pg. 675): “[t]o determine the efficacy of the anti-HSA VNAR domains to increase the serum half-life of another unrelated VNAR domain, fusions consisting of both N-terminally and C-terminally linked HSA-binding E06 to a random naïve VNAR domain known as 2V (sequence shown in Fig. 3B) were constructed…”. The anti-HSA VNAR fusion constructs increased serum half-life by over 100-fold in mice when compared to the conjugate without the anti-HSA VNAR, and the serum half-life was over 150 hours in nonhuman primates (Table 2).
Müller et al. further teaches (Discussion): “[t]he lead clone isolated exhibited the ability to improve the PK parameters of a fused tandem VNAR domain exhibiting serum half-life values equating to that of albumin itself. This study provides the potential of these single binding domains to… act as tools to improve the PK properties of other biologic proteins.”
It would have been obvious to one of ordinary skill of the art, before the effective filing date of the instant application, to have modified the conjugate claimed by Pat ‘410 in view of Müller et al. to fuse the anti-HSA VNAR of Müller et al. to the FAPα activatable protease inhibitor of Pat ‘410 (i.e., the limitations of instant claims 1 and 2) with a reasonable expectation of success, as Müller et al. teaches a method of conjugating the anti-HSA VNAR to other peptides, and the therapeutic claimed by Pat ‘410 has a peptide FAPα cleavable peptide moiety that can be fused to the anti-HSA VNAR (thus, the conjugate would have the anti-HSA VNAR conjugated to the protease inhibitor via the FAPα cleavage site). One would have been motivated to make this change to increase the half-life of the FAPα activatable protease inhibitor of Pat ‘410, which would reduce the frequency of administration and improve patient compliance and quality of life.
The combined references do not teach the conjugate comprising a cell binding moiety.
Regarding claims 3, 4, and 6, the anti-HSA VNAR of Müller et al. is a shark antibody molecule that binds to HSA, meeting the claim limitations.
Regarding claims 15, 19-21, the FAPα cleavage site claimed by Pat ‘410 is Ser-(d)Ala-Pro, meeting the claim limitations. (d)Ala-Pro is represented by the following structure recited in claim 20:
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Wherein R3 is a 1-carbon lower alkyl group.
Regarding claim 52, Pat ‘410 claims pharmaceutical compositions comprising the therapeutic and an acceptable excipient (Claim 4).
Therefore, the invention encompassed by the instant claims is a prima facie obvious variant of the invention claimed by Pat ‘410 in view of Müller et al., as evidenced by Bachovchin et al., especially in the absence of evidence to the contrary.
Claims 31-33 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-27 of U.S. Patent No. 9,597,410 (herein Pat ‘410, supra) in view of Müller et al. (supra), as evidenced by Bachovchin et al. (supra), as applied to claims 1-4, 6, 15, 19-22, 25, and 52 above, and further in view of Walsh et al. (PLoS One. 2013;8(3):e58860. doi: 10.1371/journal.pone.0058860. Epub 2013 Mar 12, supra) and Poplawski et al. (J Med Chem. 2011 Apr 14;54(7):2022-8. doi: 10.1021/jm100972f. Epub 2011 Mar 9, supra), as evidenced by MCE (Talabostat safety data sheet; file.medchemexpress.com/batch_PDF/HY-13233A/Talabostat-mesylate-SDS-MedChemExpress.pdf, supra)
The invention encompassed by instant claims 1-4, 6, 15, 19-22, 25, and 52 is a prima facie obvious variant of the invention claimed by Pat ‘410 in view of Müller et al., as evidenced by Bachovchin et al. for the reasons discussed supra. Pat ‘410 in view of Müller et al., as evidenced by Bachovchin et al. does not teach the therapeutic moiety as Val-boroPro, which is an iDASH inhibitor with acute toxicity (i.e., the limitations of claims 31-33).
The instantly claimed invention is a prima facie obvious variant of the invention claimed by Pat ‘410 in view of Müller et al., as evidenced by Bachovchin et al., and further in view of Walsh et al. and Poplawski et al., as evidenced by MCE, for the same reasons discussed in the 35 U.S.C. § 103 rejection supra.
Claims 1-4, 6, 15, 19-22, 25, and 52 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 9,956,297 (herein Pat ‘297) in view of Müller et al. (supra), as evidenced by Bachovchin et al. (supra).
Pat ‘297 claims methods of treating cancer comprising administration of FAP-activated proteasome inhibitors comprising a Ser-(d)Ala-Pro FAPα cleavable linker bound to a proteasome inhibitor (claim 2):
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Pat ‘297 does not teach the conjugates linked to half-life extension moiety.
The invention encompassed by the instant claims is a prima facie obvious variant of the invention claimed by Pat ‘297 in view of Müller et al., as evidenced by Bachovchin et al. for the same reasons discussed for Pat ‘410 supra, especially in the absence of evidence to the contrary.
Claims 31-33 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 9,956,297 (Pat ‘297, supra) in view of Müller et al. (supra), as evidenced by Bachovchin et al. (supra), as applied to claims 1-4, 6, 15, 19-22, 25, and 52 above, and further in view of Walsh et al. (supra) and Poplawski et al. (supra), as evidenced by MCE (supra)
The invention encompassed by instant claims 1-4, 6, 15, 19-22, 25, and 52 is a prima facie obvious variant of the invention claimed by Pat ‘297 in view of Müller et al., as evidenced by Bachovchin et al. for the reasons discussed supra. Pat ‘297 in view of Müller et al., as evidenced by Bachovchin et al. does not teach the therapeutic moiety as Val-boroPro, which is an iDASH inhibitor with acute toxicity (i.e., the limitations of claims 31-33).
The instantly claimed invention is a prima facie obvious variant of the invention claimed by Pat ‘297 in view of Müller et al., as evidenced by Bachovchin et al., and further in view of Walsh et al. and Poplawski et al., as evidenced by MCE, for the same reasons discussed in the 35 U.S.C. § 103 rejection supra.
Claims 1-4, 6, 15, 19-22, 25, and 52 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 10,517,955 (herein Pat ‘955) in view of Müller et al. (supra), as evidenced by Bachovchin et al. (supra).
Pat ‘955 claims methods of treatment comprising administration of FAP-activated proteasome inhibitors comprising a Ser-(d)Ala-Pro FAPα cleavable linker bound to a proteasome inhibitor (claims 12 and 18):
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Pat ‘955 does not teach the conjugates linked to half-life extension moiety.
The invention encompassed by the instant claims is a prima facie obvious variant of the invention claimed by Pat ‘955 in view of Müller et al., as evidenced by Bachovchin et al. for the same reasons discussed for Pat ‘410 supra, especially in the absence of evidence to the contrary.
Claims 31-33 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 10,517,955 (Pat ‘955, supra) in view of Müller et al. (supra), as evidenced by Bachovchin et al. (supra), as applied to claims 1-4, 6, 15, 19-22, 25, and 52 above, and further in view of Walsh et al. (supra) and Poplawski et al. (supra), as evidenced by MCE (supra)
The invention encompassed by instant claims 1-4, 6, 15, 19-22, 25, and 52 is a prima facie obvious variant of the invention claimed by Pat ‘955 in view of Müller et al., as evidenced by Bachovchin et al. for the reasons discussed supra. Pat ‘955 in view of Müller et al., as evidenced by Bachovchin et al. does not teach the therapeutic moiety as Val-boroPro, which is an iDASH inhibitor with acute toxicity (i.e., the limitations of claims 31-33).
The instantly claimed invention is a prima facie obvious variant of the invention claimed by Pat ‘955 in view of Müller et al., as evidenced by Bachovchin et al., and further in view of Walsh et al. and Poplawski et al., as evidenced by MCE, for the same reasons discussed in the 35 U.S.C. § 103 rejection supra.
Claims 1-4, 6, 15, 20-22, 25, and 52 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 11,065,339 (herein Pat ‘339) in view of Müller et al. (supra), as evidenced by Bachovchin et al. (supra).
Pat ‘339 claims pharmaceutical preparations comprising FAP-activated proteasome inhibitors with an oligopeptide FAPα cleavable group (i.e., the limitations of instant claims 15 and 20, Pat ‘339 claim 1). Pat ‘339 additionally claims the linker comprising Ser-(d)Ala (i.e., the limitations of instant claim 21, Pat ‘339 claim 1).
Pat ‘339 does not teach the conjugates linked to half-life extension moiety.
The invention encompassed by the instant claims is a prima facie obvious variant of the invention claimed by Pat ‘339 in view of Müller et al., as evidenced by Bachovchin et al. for the same reasons discussed for Pat ‘410 supra, especially in the absence of evidence to the contrary.
Claims 31-33 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 11,065,339 (Pat ‘339, supra) in view of Müller et al. (supra), as evidenced by Bachovchin et al. (supra), as applied to claims 1-4, 6, 15, 20-22, 25, and 52 above, and further in view of Walsh et al. (supra) and Poplawski et al. (supra), as evidenced by MCE (supra).
The invention encompassed by instant claims 1-4, 6, 15, 20-22, 25, and 52 is a prima facie obvious variant of the invention claimed by Pat ‘339 in view of Müller et al., as evidenced by Bachovchin et al. for the reasons discussed supra. Pat ‘339 in view of Müller et al., as evidenced by Bachovchin et al. does not teach the therapeutic moiety as Val-boroPro, which is an iDASH inhibitor with acute toxicity (i.e., the limitations of claims 31-33).
The instantly claimed invention is a prima facie obvious variant of the invention claimed by Pat ‘339 in view of Müller et al., as evidenced by Bachovchin et al., and further in view of Walsh et al. and Poplawski et al., as evidenced by MCE, for the same reasons discussed in the 35 U.S.C. § 103 rejection supra.
Claims 1-4, 6, 15, 19-22, 25, and 52 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 12,214,047 (herein Pat ‘047) in view of Müller et al. (supra), as evidenced by Bachovchin et al. (supra).
Pat ‘047 claims methods of treatment comprising administration of FAP-activated proteasome inhibitors comprising a Ser-(d)Ala-Pro FAPα cleavable linker bound to a proteasome inhibitor such as the following (claims 1 and 17):
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Pat ‘047 does not teach the conjugates linked to half-life extension moiety.
The invention encompassed by the instant claims is a prima facie obvious variant of the invention claimed by Pat ‘047 in view of Müller et al., as evidenced by Bachovchin et al. for the same reasons discussed for Pat ‘410 supra, especially in the absence of evidence to the contrary.
Claims 31-33 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 12,214,047 (Pat ‘047, supra) in view of Müller et al. (supra), as evidenced by Bachovchin et al. (supra), as applied to claims 1-4, 6, 15, 19-22, 25, and 52 above, and further in view of Walsh et al. (supra) and Poplawski et al. (supra), as evidenced by MCE (supra)
The invention encompassed by instant claims 1-4, 6, 15, 19-22, 25, and 52 is a prima facie obvious variant of the invention claimed by Pat ‘047 in view of Müller et al., as evidenced by Bachovchin et al. for the reasons discussed supra. Pat ‘047 in view of Müller et al., as evidenced by Bachovchin et al. does not teach the therapeutic moiety as Val-boroPro, which is an iDASH inhibitor with acute toxicity (i.e., the limitations of claims 31-33).
The instantly claimed invention is a prima facie obvious variant of the invention claimed by Pat ‘047 in view of Müller et al., as evidenced by Bachovchin et al., and further in view of Walsh et al. and Poplawski et al., as evidenced by MCE, for the same reasons discussed in the 35 U.S.C. § 103 rejection supra.
Claims 1-4, 6, 15, 19, 20, and 52 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 12,121,505 (herein Pat ‘505) in view of Müller et al. (supra).
Pat ‘505 claims pharmaceutical preparations comprising FAP-activated akt inhibitors with an oligopeptide FAPα cleavable group comprising (d)Ala-Pro (i.e., the limitations of instant claims 15 and 19-21, Pat ‘505 claim 3).
Pat ‘505 does not teach the conjugates linked to half-life extension moiety.
The invention encompassed by the instant claims is a prima facie obvious variant of the invention claimed by Pat ‘505 in view of Müller et al. for the same reasons discussed for Pat ‘410 supra, especially in the absence of evidence to the contrary.
Claim 21 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 12,121,505 (Pat ‘505, supra) in view of Müller et al. (supra) as applied to claims 1-4, 6, 15, 19, 20, and 52 above, and further in view of Bachovchin et al. (supra).
The invention encompassed by instant claims 1-4, 6, 15, 19, 20, and 52 is a prima facie obvious variant of the invention claimed by Pat ‘505 in view of Müller et al. for the reasons discussed supra. Pat ‘505 in view of Müller et al. does not teach the Ser-(d)Ala-Pro linker.
Bachovchin et al., in the same field of endeavor, teaches Ser-(d)Ala-Pro FAPα cleavable linker (claim 2).
It would have been obvious to substitute the Ser-(d)Ala-Pro cleavable linker of Bachovchin et al. with the (d)Ala-Pro linker of Pat ‘505 in view of Müller et al., as these are both art-recognized equivalent FAPα cleavable moieties/linkers. See Smith v. Hayashi, 209 USPQ 754 (Bd. of Pat. Inter. 1980) (The mere fact that phthalocyanine and selenium function as equivalent photoconductors in the claimed environment was not sufficient to establish that one would have been obvious over the other. However, there was evidence that both phthalocyanine and selenium were known photoconductors in the art of electrophotography. "This, in our view, presents strong evidence of obviousness in substituting one for the other in an electrophotographic environment as a photoconductor." 209 USPQ at 759.)
The invention encompassed by the instant claims is a prima facie obvious variant of the invention claimed by Pat ‘505 in view of Müller et al., and further in view of Bachovchin et al., especially in the absence of evidence to the contrary.
Claims 22 and 31-33 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 12,121,505 (Pat ‘505, supra) in view of Müller et al. (supra) as applied to claims 1-4, 6, 15, 19, 20, and 52 above, and further in view of Walsh et al. (supra) and Poplawski et al. (supra), as evidenced by MCE (supra)
The invention encompassed by instant claims 1-4, 6, 15, 19, 20, and 52 is a prima facie obvious variant of the invention claimed by Pat ‘505 in view of Müller et al. for the reasons discussed supra. Pat ‘505 in view of Müller et al. does not teach the therapeutic moiety as Val-boroPro, which is an chemotherapeutic iDASH inhibitor with acute toxicity (i.e., the limitations of claims 21 and 31-33).
The instantly claimed invention is a prima facie obvious variant of the invention claimed by Pat ‘505 in view of Müller et al., as evidenced by Bachovchin et al., and further in view of Walsh et al. and Poplawski et al., as evidenced by MCE, for the same reasons discussed in the 35 U.S.C. § 103 rejection supra.
Claim 1-4, 6, 8, 9, 15, 19-22, 25, and 52 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-6, 8-10, 12, 13, 15, 21, 22, 27, 28, 30, 36, 37, 46, and 48 of copending Application No. 18/018,208 (herein App ‘208) in view of Bachovchin et al. (supra). Although the claims at issue are not identical, they are not patentably distinct from each other.
App ‘208 claims anti-HSA stefin polypeptides that are 100% identical to instant SEQ ID NO: 110 (claims 1 and 22, SEQ ID NO: 110):
Qy 1 MIPRGLSEAKPATPEIQEIVDKVKPQLEEKTNETYGKLEAVQYKTQVLADWWQAKWPHST 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MIPRGLSEAKPATPEIQEIVDKVKPQLEEKTNETYGKLEAVQYKTQVLADWWQAKWPHST 60
Qy 61 NYYIKVRAGDNKYMHLKVFNGPYKVHQSSGGADRVLTGYQVDKNKDDELTGF 112
||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 NYYIKVRAGDNKYMHLKVFNGPYKVHQSSGGADRVLTGYQVDKNKDDELTGF 112
App ‘208 claims the anti-HSA polypeptides that have a serum half-life in human patients that is 50% or greater than serum albumin (claim 5). App ‘208 additionally claims fusion proteins comprising the anti-HSA affimer linked to a toxin (i.e., a therapeutic moiety) via a linker.
App ‘208 does not claim conjugates comprising the anti-HSA affimer half-life extension moiety linked to a therapeutic moiety via a FAPα-cleavable linker (i.e., the limitations of instant claims 1 and 2).
Bachovchin et al. teaches FAP-activated proteasome inhibitor therapeutic conjugates comprising a Ser-(d)Ala-Pro FAPα cleavable linker bound to a proteasome inhibitor (Col. 22, supra)
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Bachovchin et al. additionally teaches methods of treating cancer comprising administration of these therapeutic compounds (claims 1 and 2).
It would have been obvious to one of ordinary skill in the art to have modified the invention claimed by App ‘208 in view of Bachovchin et al. to create a conjugate comprising the anti-HSA affimers claimed by App ‘208 fused to the proteasome inhibitor taught by Bachovchin et al. via the FAPα cleavable linker with a reasonable expectation of success, as App ‘208 claims fusions of the anti-HSA affimer to polypeptides, and one with ordinary skill in the art would appreciate that the FAPα cleavable peptide that be fused to the affimer. One would have been motivated to make this change to extend the serum half-life of the conjugate to reduce the number of administrations to a patient, improving compliance and quality of life.
Regarding the functional limitations of the half-life extension moiety recited in instant claims 1 and 2, App ’208 is silent on these properties. However, both the instant application and App ‘208 claim identical anti-HSA affimers that can be used as half-life extension moieties. Given that App ‘208 claims an identical affimer as the instant application, the claimed functional outcomes would naturally and necessarily flow from using the anti-HSA affimers claimed by App ‘208 to extend the serum half-life of conjugates. One with ordinary skill in the art would expect identical affimer structures to have identical functions when used as half-life extension moieties.
Regarding claims 3, 4, 6, 8 and 9 the anti-HSA affimer claimed by App ‘208 is a nonantibody molecule that binds to HSA that is 100% identical to instant SEQ ID NO: 110, meeting the claim limitations.
Regarding claims 15 and 19-21, the FAPα cleavage site taught by Bachovchin et al. is Ser-(d)Ala-Pro, meeting the claim limitations. (d)Ala-Pro is represented by the following structure recited in instant claim 20:
PNG
media_image5.png
147
283
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Greyscale
Wherein R3 is a 1-carbon lower alkyl group.
Regarding claims 22, and 25, Bachovchin et al. teaches that the proteasome inhibitors are acutely cytotoxic once activated (Col. 40, lines 44-46): “…pro-drug version of a bortezomib-like cytotoxic agent designed to more selectively target the proteasome in solid tumors…”, meeting the claim limitations.
Regarding claim 52, Bachovchin et al. teaches pharmaceutical compositions comprising the therapeutic and an acceptable excipient (Col. 23, lines 1-4).
Therefore, the invention encompassed by the instant claims is a prima facie obvious variant of the invention claimed by App ‘280 in view of Bachovchin et al. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 31-33 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-6, 8-10, 12, 13, 15, 21, 22, 27, 28, 30, 36, 37, 46, and 48 of copending Application No. 18/018,208 (App ‘208, supra) in view of Bachovchin et al. (supra), as applied to claims 1-4, 6, 8, 9, 15, 19-22, 25, and 52 above, and further in view of Walsh et al. (supra) and Poplawski et al. (supra), as evidenced by MCE (supra)
The invention encompassed by instant claims 1-4, 6, 8, 9, 15, 19-22, 25, and 52 is a prima facie obvious variant of the invention claimed by App ‘208 in view of Bachovchin et al. for the reasons discussed supra. App ‘208 in view of Bachovchin et al. does not teach the therapeutic moiety as Val-boroPro, which is an iDASH inhibitor with acute toxicity (i.e., the limitations of claims 31-33).
The instantly claimed invention is a prima facie obvious variant of the invention claimed by App ‘208 in view of Bachovchin et al., and further in view of Walsh et al. and Poplawski et al., as evidenced by MCE, for the same reasons discussed in the 35 U.S.C. § 103 rejection supra. This is a provisional nonstatutory double patenting rejection.
Claims 1-4, 6, 8, 9, 15, 19-22, 25, 31-33, and 52 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6, 8, 9, 12, 15, 16, 19, 20, 28, 31, 34, 37, 39, 53, and 54 of copending Application No. 18/034,221 (herein App ‘221) in view of Bachovchin et al. (supra). Although the claims at issue are not identical, they are not patentably distinct from each other.
App ‘221 claims conjugates comprising an acutely toxic drug moiety linked to a half-life extension moiety via an enzyme-cleavable linker, wherein the circulating serum half-life is at least 48 hours (claim 1), or elevated by more that 2-fold relative to the drug moiety without the half-life extension moiety (claim 2).
App ‘221 claims half-life extension moieties that bind to HSA (claim 4), including affimers comprising SEQ ID NO: 110, which is 100% identical to instant SEQ ID NO: 110 (claims 6, 8, 9). App ‘221 further claims that the cleavable moieties are peptides that end in a proline (claims 15 and 16) that are cleaved by serine proteases (claims 19 and 20). App ‘221 additionally claims the therapeutic moiety can be a cytotoxic agent such as the iDASH inhibitor Val-boroPro (claims 28, 31, and 34), and compositions comprising the conjugate and an acceptable excipient. App ‘221 further claims methods of treatment comprising administration of the conjugates (claim 54).
App ‘221 does not claim conjugates comprising a FAPα cleavable linker such as Ser-(d)Ala-Pro.
Bachovchin et al., in the same field of endeavor, teaches FAPα cleavable peptides that can be used to make drug conjugates that are selectively activated by FAPα for site-specific drug release a FAPα+ tumor sites (Col. 21, lines 59-66). Bachovchin et al. provides motivation to make such conjugates to reduce toxic side-effects of therapeutic drugs (Col. 5, lines 40-65): “[t]he compounds of the present invention are designed to remain inactive in healthy organs and to be activated by the tumor-associated enzyme called fibroblast activation protein (FAP)…”.
It would have been obvious to one with ordinary skill in the art to have modified the invention of App ‘221 in view of Bachovchin et al. to make therapeutic conjugates comprising an acutely toxic therapeutic moiety linked to a half-life extension moiety via a FAPα cleavable linker such as Ser-(d)Ala-Pro with a reasonable expectation of success, as App ‘221 is claiming serine protease cleavable linkers and Bachovchin et al. teaches that Ser-(d)Ala-Pro is a suitable FAPα cleavable linker. One would have been motivated to make this change to create FAPα activatable therapeutic conjugates that are targeted to the tumor microenvironment, leading to tumor site-specific drug activation and lower side effects in a patient.
The instantly claimed invention is a prima facie obvious variant of the invention claimed by App ‘221 in view of Bachovchin et al. This is a provisional nonstatutory double patenting rejection.
Claims 1-4, 6, 15, 19, 20, 22, and 52 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 65 and 74-93 of copending Application No. 17/554,823 (herein App ‘823) in view of Müller et al. (supra). Although the claims at issue are not identical, they are not patentably distinct from each other.
App ‘823 claims prodrug radiotherapeutics comprising a (d)Ala-Pro FAPα cleavable linker and a cytotoxic radiotheranostic chelation moiety (i.e., “a drug moiety”; claims 65, 74, and 85).
App ‘823 does not teach the conjugates linked to half-life extension moiety.
The invention encompassed by the instant claims is a prima facie obvious variant of the invention claimed by App ‘823 in view of Müller et al. for the same reasons discussed for Pat ‘410 supra, especially in the absence of evidence to the contrary. This is a provisional nonstatutory double patenting rejection.
Claim 21 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 65 and 74-93 of copending Application No. 17/554,823 (App ‘823, supra) in view of Müller et al. (supra) as applied to claims 1-4, 6, 15, 19, 20, 22, and 52 above, and further in view of Bachovchin et al. (supra).
The invention encompassed by instant claims 1-4, 6, 15, 19, 20, 22, and 52 is a prima facie obvious variant of the invention claimed by App ‘823 in view of Müller et al. for the reasons discussed supra. App ‘823 in view of Müller et al. does not teach the Ser-(d)Ala-Pro linker.
The invention encompassed by the instant claims is a prima facie obvious variant of the invention claimed by App ‘823 in view of Müller et al. and further in view of Bachovchin et al. for the same reasons discussed for Pat ‘505 supra. This is a provisional double patenting rejection.
Claims 25 and 31-33 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 65 and 74-93 of copending Application No. 17/554,823 (App ‘823, supra) in view of Müller et al. (supra), as applied to claims 1-4, 6, 15, 19, 20, 22, and 52 above, and further in view of Walsh et al. (supra) and Poplawski et al. (supra), as evidenced by MCE (supra)
The invention encompassed by instant claims 1-4, 6, 15, 19, 20, 22, 25, and 52 is a prima facie obvious variant of the invention claimed by App ‘823 in view of Müller et al. for the reasons discussed supra. App ‘823 in view of Müller et al. does not teach the therapeutic moiety as Val-boroPro, which is an iDASH inhibitor with acute toxicity (i.e., the limitations of claims 25 and 31-33).
The instantly claimed invention is a prima facie obvious variant of the invention claimed by App ‘823 in view of Müller et al., and further in view of Walsh et al. and Poplawski et al., as evidenced by MCE, for the same reasons discussed in the 35 U.S.C. § 103 rejection supra. This is a provisional nonstatutory double patenting rejection.
Claims 1-4, 6, 15, 19-22, 25, 31-33, and 52 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 13-15, 23, 24, 28, 31, 78, 79, 85, 86, 88, 89, 90, and 94-98 of copending Application No. 15/734,445 (herein App ‘445) in view of Bachovchin et al. (supra) and Müller et al. (supra). Although the claims at issue are not identical, they are not patentably distinct from each other.
App ‘445 claims therapeutic conjugates comprising a cell-binding moiety that binds to PD-L1, a linker, a substrate recognition sequence, a second linker, and a drug moiety (claim 1). App ‘445 claims the SRS is a FAPα cleavable linker comprising (d)Ala-Pro (claim 1 wherein X is O, R2 is H, R3 is a 1C alkyl, and R4 is a 3C alkyl; the limitations of instant claims 19 and 20). App ‘445 further claims the drug moiety can be Val-boroPro (claim 86; the limitations of instant claims 22, 25, and 31-33). App ‘445 claims pharmaceutical compositions comprising the conjugate and an acceptable excipient (claim 78).
Bachovchin et al., in the same field of endeavor, teaches that FAPα activatable therapeutics do not need a cell binding moiety to be targeted to tumor sites (Col. 5, lines 46-54): “[t]he compounds of the present invention are designed to remain inactive in healthy organs and to be activated by the tumor-associated enzyme called fibroblast activation protein (FAP)…” Bachovchin et al. further teaches that Ser-(d)Ala-Pro is another FAP-cleavable linker (bottom of Col. 22).
Neither App ‘445 nor Bachovchin et al. teach the conjugates linked to half-life extension moiety
The teachings of Müller et al. have been discussed supra.
It would have been obvious to one of ordinary skill of the art, before the effective filing date of the instant application, to have modified the conjugate claimed by App ‘445 in view of Bachovchin et al. and Müller et al. to remove the cell-binding moiety from the claimed therapeutic conjugates claimed by App ‘445 and fuse the anti-HSA VNAR of Müller et al. to the FAPα activatable protease inhibitor of App ‘445 (i.e., the limitations of instant claims 1 and 2) with a reasonable expectation of success, as Bachovchin et al. teaches that FAP-targeted therapeutics do not need an additional cell binding moiety and Müller et al. teaches a method of conjugating the anti-HSA VNAR to other peptides, and the therapeutic claimed by App ‘445 has a peptide FAPα cleavable peptide moiety that can be fused to the anti-HSA VNAR (thus, the conjugate would have the anti-HSA VNAR conjugated to the protease inhibitor via the FAPα cleavage site). One would have been motivated to make these changes to allow the drug moiety to target all FAP-expressing cancers, not just FAP and PD-L1 expressing cancer and to increase the half-life of the FAPα activatable protease inhibitor of App ‘445, which would reduce the frequency of administration and improve patient compliance and quality of life and allow the therapeutic to target more cancers.
Claim 25 is included because Bachovchin et al. teaches a Ser can be added to the (d)Ala-Pro cleavable linker.
Therefore, the invention encompassed by the instant claims is a prima facie obvious variant of the invention claimed by App ‘445 in view of Pat ‘955 in view of Bachovchin et al. and Müller et al., especially in the absence of evidence to the contrary. This is a provisional double patenting rejection.
Conclusion
No claim is allowed.
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/ALEC JON PETERS/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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