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 .
Claims 1, 8, 17-20, 23, 31, 42, 49-50, 57-58, 62-64, 66-68 and 72 are pending and will be examined on the merits.
Claim Rejections - 35 USC § 112
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.
Claim 17, 19-20, 23, 31, 49-50 and 57 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.
Claims 17, 19-20, 23 and 31
Claims 17, 19-20, 23 and 31 are directed conjugates wherein the CIDE has the structure:
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None of the permissible moieties for any of the “L1-XXX” groups contained within parentheses (L1-Q, L1-T, L1-U, etc….) are defined. Additionally, the claims recite different structural loci on BRM or E3LB (e.g., “L1Q is at (insert chemical structure) on BRM”). However, there are no recitations of the chemical structure of BRM or E3LB in either claim 17 or claim 1 (claim 17 is dependent on claim 1), rendering it impossible to determine where on the CIDE any of the L1-XXX groups are located. The lack of permissible moieties for the L1-XXX groups coupled with lack of known structure for the CIDE sufficient to determine the position(s) of the L1-XXX group each independently render the metes and bounds of the claims unclear and thus indefinite.
Claims 49-50
Claim 49 is dependent on claim 1 and claim 49 recites the limitation "
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" in the body of the claim. There is insufficient antecedent basis for this limitation in the claim.
Additionally, the three connections extending from the BRM module recited in claim 49 conflicts with the description of the BRM module as recited in claim 1, where the BRM module is recited as a component of the CIDE of claim 1, with the CIDE structure recited in claim 1 being:
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Claim 1 also recites that the CIDE depicted above is attached to an antibody via an L1 linker moiety attached to BRM, L2 or E3LB. As such, the BRM module recited in claim 1 comprises, at most two connections: 1) one connection to E3LB via L2 and 2) one connection to the antibody via L1 (in the case where the antibody is connected to the CIDE via the BRM module). The inclusion of the third connection extending from the BRM module recited in claim 49 additionally renders the metes and bounds of the claims unclear because it is unclear what, if anything the third connection extending from the BRM module recited in claim 49 must connect to in order to satisfy the limitations of the structure.
Note: for the purposes of examination, claims 49-50 will be examined as if the BRM module of claim 1 (the one depicted above with the red arrow) was recited in the preamble of claim 49 instead of
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Claim 57
Regarding claim 57, claim 57 is dependent on claim 1 and claim 57 recites several chemical structures, all of which comprise “L1-Q” variable groups. The definition of and permissible moieties for these “L1-Q” variable groups are not defined in either claim 57 or claim 1. As such the metes and bounds of the claim are unclear and therefore indefinite.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
Claim(s) 1, 8, 18, 42, 58, 49-50, 62-64, 66-68 and 72 is/are rejected under 35 U.S.C. 103 as being unpatentable over Crew (Crew, et al., US 2019/0300521 A1; Published 10/3/2019; Priority to 1/28/2019 via US 62/797,754) in view of Dragovich (Dragovich, et al., WO2020/086858; published 4/30/2020; Priority to 10/24/2018 via US 62/749,812) and Palata (Palata, et al., Immunol. Lett. 2020 46-53).
Crew teaches on the subject of BRM-targeting ubiquitin degrading molecules (same as CIDE) (Crew, Abstract). Crew teaches that the BRM-targeting CIDEs of Crew cause the degradation of BRM and are administered in methods of treating SMARCA4-related/deficient cancers, including lung cancer and non-small cell lung cancer (Crew, ¶ 0010). Crew teaches that the BRM-targeting CIDEs of Crew comprise the structure (Crew, p 238):
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Please note that the structure above fully satisfies structure L2a recited in claim 58 as well as the complete structure of L1-CIDE-BRM1-22 recited in claim 62 prior to L1 attachment.
Crew does not teach that the BRM-targeting CIDE is conjugated to an antibody via a linker with a DAR from about 5 to about 10, wherein the BRM-targeting CIDE-antibody conjugate comprises the second structure of claim 64, or pharmaceutical compositions thereof. Crew does not teach that the BRM-targeting CIDE is conjugated to an antibody via a linker with a DAR from about 5 to about 10, wherein the drug-linker component of the BRM-targeting CIDE-antibody conjugate comprises the second structure of claim structure L1-CIDE-BRM1-20 of claim 62 prior to conjugation to the antibody, or pharmaceutical compositions thereof. Crew does not teach a method of treating a disease in a human in need thereof comprising the administration of BRM-targeting CIDE-antibody conjugate. Crew does not teach a method of reducing the level of BRM in a subject comprising administering to said subject a BRM-targeting CIDE-antibody conjugate.
Dragovich teaches on the subject of antibody-CIDE conjugates having the formula Ab-(L1-D)p, wherein D is a CIDE having the structure E3LB-L2-PB, E3LB is a group that binds the VHL E3 ligase, L1 and L2 is are linkers, Ab is an antibody, p is a value from about 1 to about 8 and PB is a protein-binding group that binds BRD4 or ER-alpha as well as methods of treating disease comprising administering pharmaceutical compositions comprising such antibody-CIDE conjugates (Dragovich, p2, ¶ 5 – p 3, ¶ 5). Dragovich teaches that a CIDE-linker-crosslinker moiety having the following structure (Dragovich, p 417, ¶ 1).:
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Dragovich teaches that a CIDE-linker-crosslinker moiety having the following structure (Dragovich, p 461, ¶ 1):
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Dragovich also teaches that the antibody of the antibody-CIDE conjugates of Dragovich is a HER2 antibody (Dragovich, claim 13).
Palata teaches that HER2 is a known NSCLC tumor-associated antigen (Palata, Abstract).
It would be prima facie obvious to one of ordinary skill in the art to combine the BRM-targeting CIDE of Crew with the anti-HER2 CIDE-antibody conjugate of Dragovich comprising the diphosphate L1 linker attached at the hydroxyl of the VHL binding moiety to form an anti-HER2 antibody-BRM-targeting CIDE conjugate identical to the second structure of claim 64 with a DAR of about 5 and administer the resultant conjugate in methods of treating NSCLC, wherein administration reduces the level of BRM in the subject in view of the teachings of Palata. One of ordinary skill in the art would be motivated to do this in order to better treat NSCLC. One of ordinary skill in the art would have a reasonable expectation of success combining the BRM-targeting CIDE of Crew with the anti-HER2 CIDE-antibody conjugate of Dragovich comprising the diphosphate L1 linker attached at the hydroxyl of the VHL binding moiety to form an anti-HER2 antibody-BRM-targeting CIDE conjugate identical to the second structure of claim 64 with a DAR of about 5 and administering the resultant conjugate in methods of treating NSCLC, wherein administration reduces the level of BRM in the subject in view of the teachings of Palata because: 1) Crew teaches a BRM-targeting CIDE identical to the second structure of claim 64 except for the methyl group present in the 6-member ring of L2, 2) Crew also teaches administration of BRM-targeting CIDEs as a method of treating NSCLC, 3) Dragovich teaches the diphosphate-comprising maleimide linker is a suitable for linking a nearly identical VHL E3 binding moiety to anti-HER2 antibody via a hydroxyl group, 4) Dragovich teaches CIDE-antibody conjugates having DAR between 1-8 and arriving at a DAR of about 5 is a matter of routine experimentation, which is in the purview of one of skill in the art, 5) Palata teaches that HER2 is a known NSCLC tumor-associated antigen and 6) one of ordinary skill in the art would reasonably therefor expect the resultant anti-HER2 BRM-targeting CIDE-antibody conjugate to localize the BRM-targeting CIDE of Crew to NSCLC cells via binding to HER2, where the BRM-targeting CIDE of Crew would treat the NSCLC by causing BRM degradation (same as reducing levels of BRM).
Regarding the methyl group present on the six-membered ring present in L2 in the instant claims, it is generally noted that the substitution of methyl for hydrogen on a known compound is not a patentable modification absent unexpected or unobvious results. In re Lincoln, 126 U.S.P.Q. 477, 53 U.S. P.Q. 40 (C.C.P.A. 1942); In re Druey, 319 F.2d 237, 138 U.S.P.Q. 39 (C.C. P.A. 1963); In re Lohr, 317 F.2d 388, 137 U.S.P.Q. 548 (C.C.P.A. 1963); In re Hoehsema, 399 F.2d 269, 158 U.S.P.Q. 598 (C.C.P.A. 1968); In re Wood, 582 F.2d 638, 199 U.S. P.Q. 137 (C.C.P.A. 1978); In re Hoke, 560 F.2d 436, 195 U.S.P.Q. 148 (C.C.PA.A. 1977); Ex parte Fauque, 121 U.S.P.Q. 425 (P.O.B.A. 1954); Ex parte Henkel, 130 U.S.P.Q. 474, (P.O.B.A. 1960). Given that applicant did not provide unexpected or unobvious results of the invention, it is concluded that the normal desire of scientists or artisans to improve upon what is already generally known would provide the motivation to substitute the “H” group to a “methyl”. Please note that this combination fully satisfies all of claims 1, 8, 18, 42, 49-50, 58, 63-64, 66-68 and 72.
It would be prima facie obvious to one of ordinary skill in the art to combine the BRM-targeting CIDE of Crew with the anti-HER2 CIDE-antibody conjugate of Dragovich comprising the cyclobutene-comprising L1 linker attached at the a primary aromatic amine on the CIDE of Dragovich to form an anti-HER2 antibody-BRM-targeting CIDE conjugate wherein the drug-linker is identical to L1-CIDE-BRM1-20 of claim 62 prior to antibody conjugation with a DAR of about 5 and administer the resultant conjugate in methods of treating NSCLC, wherein administration reduces the level of BRM in the subject in view of the teachings of Palata. One of ordinary skill in the art would be motivated to do this in order to better treat NSCLC. One of ordinary skill in the art would have a reasonable expectation of success combining the BRM-targeting CIDE of Crew with the anti-HER2 CIDE-antibody conjugate of Dragovich comprising the cyclobutene-comprising L1 linker attached at the a primary aromatic amine on the CIDE of Dragovich to form an anti-HER2 antibody-BRM-targeting CIDE conjugate wherein the drug-linker is identical to L1-CIDE-BRM1-20 of claim 62 prior to antibody conjugation and wherein the antibody-CIDE conjugate has a DAR of about 5 and administer the resultant conjugate in methods of treating NSCLC, wherein administration reduces the level of BRM in the subject in view of the teachings of Palata because: 1) Crew teaches a BRM-targeting CIDE identical to L1-CIDE-BRM1-20 of claim 62 except for the methyl group present in the 6-member ring of L2, 2) Crew also teaches administration of BRM-targeting CIDEs as a method of treating NSCLC, 3) Dragovich teaches the cyclobutane-comprising maleimide linker is a suitable for linking CIDEs to antibodies via primary aromatic amines and there is a single primary aromatic amine on the BRM-targeting CIDE of Crew, 4) Dragovich teaches CIDE-antibody conjugates having DAR between 1-8 and arriving at a DAR of about 5 is a matter of routine experimentation, which is in the purview of one of skill in the art, 5) Palata teaches that HER2 is a known NSCLC tumor-associated antigen and 6) one of ordinary skill in the art would reasonably therefor expect the resultant anti-HER2 BRM-targeting CIDE-antibody conjugate to localize the BRM-targeting CIDE of Crew to NSCLC cells via binding to HER2, where the BRM-targeting CIDE of Crew would treat the NSCLC by causing BRM degradation (same as reducing levels of BRM).
Regarding the methyl group present on the six-membered ring present in L2 in the instant claims, it is generally noted that the substitution of methyl for hydrogen on a known compound is not a patentable modification absent unexpected or unobvious results. In re Lincoln, 126 U.S.P.Q. 477, 53 U.S. P.Q. 40 (C.C.P.A. 1942); In re Druey, 319 F.2d 237, 138 U.S.P.Q. 39 (C.C. P.A. 1963); In re Lohr, 317 F.2d 388, 137 U.S.P.Q. 548 (C.C.P.A. 1963); In re Hoehsema, 399 F.2d 269, 158 U.S.P.Q. 598 (C.C.P.A. 1968); In re Wood, 582 F.2d 638, 199 U.S. P.Q. 137 (C.C.P.A. 1978); In re Hoke, 560 F.2d 436, 195 U.S.P.Q. 148 (C.C.PA.A. 1977); Ex parte Fauque, 121 U.S.P.Q. 425 (P.O.B.A. 1954); Ex parte Henkel, 130 U.S.P.Q. 474, (P.O.B.A. 1960). Given that applicant did not provide unexpected or unobvious results of the invention, it is concluded that the normal desire of scientists or artisans to improve upon what is already generally known would provide the motivation to substitute the “H” group to a “methyl”. Please note that this combination fully satisfies all of claims 1, 8, 18, 42, 49-50, 58, 62, 66-68 and 72.
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, 8, 18, 42, 49-50, 58, 62-64, 66-68 and 72 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 12440706 B2 in view of Crew (Crew, et al., US 2019/0300521 A1; Published 10/3/2019; Priority to 1/28/2019 via US 62/797,754), Dragovich (Dragovich, et al., WO2020/086858; published 4/30/2020; Priority to 10/24/2018 via US 62/749,812) and Palata ().
The ’706 patent teaches on the subject of antibody-CIDE conjugates having the formula Ab-(L1-D)p, wherein D is a CIDE having the structure E3LB-L2-PB, E3LB is a group that binds the VHL E3 ligase, L1 and L2 is are linkers, Ab is an antibody, p is a value from about 1 to about 8 and PB is a protein-binding group that binds BRD4 or ER-alpha (patented claim 1) as well as methods of treating disease comprising administering compositions comprising such antibody-CIDE conjugates and pharmaceutical compositions of the antibody-CIDE conjugates of the ‘706 patent (patented claims 12-13). The ‘706 patent teaches a CIDE linked to the following CIDE-linker-crosslinker moiety (patented claim 7):
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The ‘706 patent does not teach that the BRM-targeting CIDE is conjugated to an antibody via a linker with a DAR from about 5 to about 10, wherein the BRM-targeting CIDE-antibody conjugate comprises the first structure of claim 64, or pharmaceutical compositions thereof. The ‘706 patent does not teach that the BRM-targeting CIDE is conjugated to an antibody via a linker with a DAR from about 5 to about 10, wherein the drug-linker component of the BRM-targeting CIDE-antibody conjugate comprises the second structure of claim structure L1-CIDE-BRM1-7 of claim 62 prior to conjugation to the antibody, or pharmaceutical compositions thereof. The ‘706 patent does not teach a method of treating a disease in a human in need thereof comprising the administration of BRM-targeting CIDE-antibody conjugate. The ‘706 patent does not teach a method of reducing the level of BRM in a subject comprising administering to said subject a BRM-targeting CIDE-antibody conjugate.
Crew teaches on the subject of BRM-targeting ubiquitin degrading molecules (same as CIDE) (Crew, Abstract). Crew teaches that the BRM-targeting CIDEs of Crew cause the degradation of BRM and are administered in methods of treating SMARCA4-related/deficient cancers, including lung cancer and non-small cell lung cancer (Crew, ¶ 0010). Crew teaches that the BRM-targeting CIDEs of Crew comprise the structure (Crew, p 238):
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Dragovich teaches on the subject of antibody-CIDE conjugates having the formula Ab-(L1-D)p, wherein D is a CIDE having the structure E3LB-L2-PB, E3LB is a group that binds the VHL E3 ligase, L1 and L2 is are linkers, Ab is an antibody, p is a value from about 1 to about 8 and PB is a protein-binding group that binds BRD4 or ER-alpha as well as methods of treating disease comprising administering pharmaceutical compositions comprising such antibody-CIDE conjugates (Dragovich, p2, ¶ 5 – p 3, ¶ 5).
Dragovich also teaches that the antibody of the antibody-CIDE conjugates of Dragovich is a HER2 antibody (Dragovich, claim 13).
Palata teaches that HER2 is a known NSCLC tumor-associated antigen (Palata, Abstract).
It would be prima facie obvious to one of ordinary skill in the art to combine the BRM-targeting CIDE of Crew with the CIDE-antibody conjugate of the ‘706 patent comprising the dimethylated sulfide linker attached at a hydroxyl group and the anti-HER2 antibody of Dragovich form an anti-HER2 antibody-BRM-targeting CIDE conjugate wherein the drug-linker is identical to the first structure of claim 64 with DAR of about 5 and administer the resultant conjugate in methods of treating NSCLC, wherein administration reduces the level of BRM in the subject in view of the teachings of Palata. One of ordinary skill in the art would be motivated to do this in order to better treat NSCLC. One of ordinary skill in the art would have a reasonable expectation of success
combining the BRM-targeting CIDE of Crew with the CIDE-antibody conjugate of the ‘706 patent comprising the dimethylated sulfide linker attached at a hydroxyl group and the anti-HER2 antibody of Dragovich form an anti-HER2 antibody-BRM-targeting CIDE conjugate wherein the drug-linker is identical to the first structure of claim 64 with DAR of about 5 and administer the resultant conjugate in methods of treating NSCLC, wherein administration reduces the level of BRM in the subject in view of the teachings of Palata because: 1) Crew teaches a BRM-targeting CIDE identical to the CIDE component of the first structure of claim 64 except for the methyl group present in the 6-member ring of L2, 2) Crew also teaches administration of BRM-targeting CIDEs as a method of treating NSCLC, 3) the ‘706 patent teaches an L1 moiety identical to the L1 moiety of the first structure of claim 64 is suitable for linking a nearly identical VHL E3 binding moiety to antibodies via a hydroxyl group, 4) the ‘706 patent teaches CIDE-antibody conjugates having DAR between 1-8 and arriving at a DAR of about 5 is a matter of routine experimentation, which is in the purview of one of skill in the art, 5) Dragovich teaches conjugation of CIDEs to anti-HER2 antibodies, 6) Palata teaches that HER2 is a known NSCLC tumor-associated antigen and 7) one of ordinary skill in the art would reasonably therefor expect the resultant anti-HER2 BRM-targeting CIDE-antibody conjugate to localize the BRM-targeting CIDE of Crew to NSCLC cells via binding to HER2, where the BRM-targeting CIDE of Crew would treat the NSCLC by causing BRM degradation (same as reducing levels of BRM).
Regarding the methyl group present on the six-membered ring present in L2 in the instant claims, it is generally noted that the substitution of methyl for hydrogen on a known compound is not a patentable modification absent unexpected or unobvious results. In re Lincoln, 126 U.S.P.Q. 477, 53 U.S. P.Q. 40 (C.C.P.A. 1942); In re Druey, 319 F.2d 237, 138 U.S.P.Q. 39 (C.C. P.A. 1963); In re Lohr, 317 F.2d 388, 137 U.S.P.Q. 548 (C.C.P.A. 1963); In re Hoehsema, 399 F.2d 269, 158 U.S.P.Q. 598 (C.C.P.A. 1968); In re Wood, 582 F.2d 638, 199 U.S. P.Q. 137 (C.C.P.A. 1978); In re Hoke, 560 F.2d 436, 195 U.S.P.Q. 148 (C.C.PA.A. 1977); Ex parte Fauque, 121 U.S.P.Q. 425 (P.O.B.A. 1954); Ex parte Henkel, 130 U.S.P.Q. 474, (P.O.B.A. 1960). Given that applicant did not provide unexpected or unobvious results of the invention, it is concluded that the normal desire of scientists or artisans to improve upon what is already generally known would provide the motivation to substitute the “H” group to a “methyl”. Please note that this combination fully satisfies all of claims 1, 8, 18, 42, 49-50, 58, 63-64, 66-68 and 72. In the same manner, the only difference between the combined compound just discussed and L1-CIDE-BRM1-7 of claim 62 is one additional methyl group on L1 and, as such the substation of the hydrogen on L1 in favor of an additional methyl group is also an obvious combination for the reasons just discussed and this additionally reads on claim 62.
Claim 1, 8, 18, 42, 49-50, 58, 62-64, 66-68 and 72 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-63 of copending Application No. 19/248,849 (not yet published) in view of Crew (Crew, et al., US 2019/0300521 A1; Published 10/3/2019; Priority to 1/28/2019 via US 62/797,754) and Palata (Palata, et al., Immunol. Lett. 2020 46-53).
The ‘849 application teaches on the subject of antibody-CIDE conjugates having the formula Ab-(L1-D)p, wherein D is a CIDE having the structure E3LB-L2-PB, E3LB is a group that binds the VHL E3 ligase, L1 and L2 is are linkers, Ab is an antibody, p is a value from about 1 to about 8 and PB is a protein-binding group that binds BRD4 or ER-alpha (copending claim 1) as well as methods of treating disease comprising administering compositions comprising such antibody-CIDE conjugates and pharmaceutical compositions of the antibody-CIDE conjugates of the ‘849 application (copending claims 58-59). The ‘849 application teaches a CIDE linked to the following CIDE-linker-crosslinker moiety (copending claim 57):
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The ‘849 application also teaches that the antibody of the antibody-CIDE conjugate binds HER2 (copending claim 20)
The ‘849 application does not teach that the BRM-targeting CIDE is conjugated to an antibody via a linker with a DAR from about 5 to about 10, wherein the BRM-targeting CIDE-antibody conjugate comprises the first structure of claim 64, or pharmaceutical compositions thereof. The ‘849 application does not teach that the BRM-targeting CIDE is conjugated to an antibody via a linker with a DAR from about 5 to about 10, wherein the drug-linker component of the BRM-targeting CIDE-antibody conjugate comprises the second structure of claim structure L1-CIDE-BRM1-7 of claim 62 prior to conjugation to the antibody, or pharmaceutical compositions thereof. The ‘849 application does not teach a method of treating a disease in a human in need thereof comprising the administration of BRM-targeting CIDE-antibody conjugate. The ‘849 application does not teach a method of reducing the level of BRM in a subject comprising administering to said subject a BRM-targeting CIDE-antibody conjugate.
Crew teaches on the subject of BRM-targeting ubiquitin degrading molecules (same as CIDE) (Crew, Abstract). Crew teaches that the BRM-targeting CIDEs of Crew cause the degradation of BRM and are administered in methods of treating SMARCA4-related/deficient cancers, including lung cancer and non-small cell lung cancer (Crew, ¶ 0010). Crew teaches that the BRM-targeting CIDEs of Crew comprise the structure (Crew, p 238):
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Palata teaches that HER2 is a known NSCLC tumor-associated antigen (Palata, Abstract).
It would be prima facie obvious to one of ordinary skill in the art to combine the BRM-targeting CIDE of Crew with the anti-HER2 CIDE-antibody conjugate of the ‘849 application comprising the dimethylated sulfide linker attached at a hydroxyl group to form an anti-HER2 antibody-BRM-targeting CIDE conjugate wherein the drug-linker is identical to the first structure of claim 64 with DAR of about 5 and administer the resultant conjugate in methods of treating NSCLC, wherein administration reduces the level of BRM in the subject in view of the teachings of Palata. One of ordinary skill in the art would be motivated to do this in order to better treat NSCLC. One of ordinary skill in the art would have a reasonable expectation of success combining the BRM-targeting CIDE of Crew with the anti-HER2 CIDE-antibody conjugate of the ‘849 application comprising the dimethylated sulfide linker attached at a hydroxyl group an anti-HER2 antibody-BRM-targeting CIDE conjugate wherein the drug-linker is identical to the first structure of claim 64 with DAR of about 5 and administer the resultant conjugate in methods of treating NSCLC, wherein administration reduces the level of BRM in the subject in view of the teachings of Palata because: 1) Crew teaches a BRM-targeting CIDE identical to the CIDE component of the first structure of claim 64 except for the methyl group present in the 6-member ring of L2, 2) Crew also teaches administration of BRM-targeting CIDEs as a method of treating NSCLC, 3) the ‘849 application teaches an L1 moiety identical to the L1 moiety of the first structure of claim 64 is suitable for linking a nearly identical VHL E3 binding moiety to antibodies via a hydroxyl group, 4) the ‘849 application teaches anti-HER2 CIDE-antibody conjugates having DAR between 1-8 and arriving at a DAR of about 5 is a matter of routine experimentation, which is in the purview of one of skill in the art, 5) Palata teaches that HER2 is a known NSCLC tumor-associated antigen and 6) one of ordinary skill in the art would reasonably therefor expect the resultant anti-HER2 BRM-targeting CIDE-antibody conjugate to localize the BRM-targeting CIDE of Crew to NSCLC cells via binding to HER2, where the BRM-targeting CIDE of Crew would treat the NSCLC by causing BRM degradation (same as reducing levels of BRM).
Regarding the methyl group present on the six-membered ring present in L2 in the instant claims, it is generally noted that the substitution of methyl for hydrogen on a known compound is not a patentable modification absent unexpected or unobvious results. In re Lincoln, 126 U.S.P.Q. 477, 53 U.S. P.Q. 40 (C.C.P.A. 1942); In re Druey, 319 F.2d 237, 138 U.S.P.Q. 39 (C.C. P.A. 1963); In re Lohr, 317 F.2d 388, 137 U.S.P.Q. 548 (C.C.P.A. 1963); In re Hoehsema, 399 F.2d 269, 158 U.S.P.Q. 598 (C.C.P.A. 1968); In re Wood, 582 F.2d 638, 199 U.S. P.Q. 137 (C.C.P.A. 1978); In re Hoke, 560 F.2d 436, 195 U.S.P.Q. 148 (C.C.PA.A. 1977); Ex parte Fauque, 121 U.S.P.Q. 425 (P.O.B.A. 1954); Ex parte Henkel, 130 U.S.P.Q. 474, (P.O.B.A. 1960). Given that applicant did not provide unexpected or unobvious results of the invention, it is concluded that the normal desire of scientists or artisans to improve upon what is already generally known would provide the motivation to substitute the “H” group to a “methyl”. Please note that this combination fully satisfies all of claims 1, 8, 18, 42, 49-50, 58, 63-64, 66-68 and 72. In the same manner, the only difference between the combined compound just discussed and L1-CIDE-BRM1-7 of claim 62 is one additional methyl group on L1 and, as such the substation of the hydrogen on L1 in favor of an additional methyl group is also an obvious combination for the reasons just discussed and this additionally reads on claim 62.
This is a provisional nonstatutory double patenting rejection.
Conclusion
Claims 1, 8, 17-20, 23, 31, 42, 49-50, 57-58, 62-64, 66-68 and 72 are rejected.
No claims are allowed.
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/SYDNEY VAN DRUFF/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643