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 .
Priority
The application claims priority to provisional application 63/166716, filed on 26 March 2021, and is 371 of PCT/US2022/021969, filed on 25 March 2022. The effective filing date is 26 March 2021.
Information Disclosure Statement
The information disclosure statement (IDS), submitted on 15 April 2024, was considered by the examiner.
Election/Restrictions
In response to the election of species requirement, issued on 29 April 2026, the applicant elected without traverse the 2-amino-4-carboxamide-benzazepine-linker compound 2Am4CBzL-18, depicted on page 59 of the specification and claim 34:
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Claims 1, 12-15, 18, 26-28, 32, 34-39, 42, 44-48, 52-54, 57, 59, 61, 63, and 64 encompass the elected invention. Claims 10, 11, 16, 23-25, 31, 33, 55, 56, 58, 60, and 62 are withdrawn from consideration. Claims 1, 12-15, 18, 26-28, 32, 34-39, 42, 44-48, 52-54, 57, 59, 61, 63, and 64 are pending and the subject of this office action.
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.
Claims 1, 12-15, 18, 26-28, 32, 35, 36-39, 42, 44-48, 52-54, 57, 59, 61, and 63 are rejected under 35 U.S.C. 103 as being unpatentable over US20180258048 A1 (herein Coburn) in view of EP 0 825 186 A1 (herein Cooper), both of which were presented in the IDS submitted on 15 April 2024, with Kieffer ME, et al. (2020) Small molecule agonists of toll-like receptors 7 and 8: a patent review 2014 - 2020. Expert Opin Ther Pat. 2020 Nov;30(11):825-845 (herein Kieffer) providing additional evidentiary value.
In regard to claims 1 and 48, Coburn relates to benzazepine compounds, conjugates, and pharmaceutical compositions for use in the treatment of disease (Abstract). The authors describe that the disclosed inventions may be used to activate immune response, via TLR8 agonism, in treatment methods for various forms of cancer, including colon cancer, breast cancer, lung cancer (including non-small cell lung cancer), Merkel cell carcinoma, bladder, etc (Relevant to instant claims 37-39) ([0561-0563]). Coburn teaches that the disclosed inventions, comprise compounds (i.e. benzazepine derivatives), that selectively modulate the activity of one toll-like receptor over another ([0462]). The example describes a compound, which binds TLR8 with a higher affinity than that of TLF7. Coburn teaches conjugates comprising a benzazepine derivative (D), a linker moiety (L), and an antibody, as depicted in the following formula (Relevant to instant claims 1 and 42) ([0111]):
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In regard to the nature of the antibody, claims and working examples of embodiments comprising CEA (figures 3 and 4), HER2 ([0110], figures 1, 9, and 10), Claim 18), and TROP2 ([0110], Claim 18, and figures 2, 7, 8) are taught, as well as antibody constructs comprising trastuzumab, pertuzumab, or sacituzumab (Relevant to instant claims 45 and 46) (Claim 19, and [0110]). Pharmaceutical compositions comprising conjugate and one or more carrier, diluent, excipient, stabilizer, dispersing agent, suspending agent, and or thickening agent are taught (Relevant to instant claim 36) ([0540]). It is taught that the linker (L3) may be covalently bound to positions corresponding to R4 of the benzazepine core structures shown below ([0262] and [0288]):
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Within this disclosure the authors teach that various methods that may be used to form “linker-payloads”, in which immune-stimulating compounds (i.e. benzazepine derivatives) are covalently attached to various bifunctional linkers ([0570-0579]). Several of the provided examples, teach limitations described in instant claims 48, 59, and 61, regarding the nature of L-Q in the instant claims. For example, scheme 5-3 ([0574-0575]), teaches the formation of an immune-stimulating linker compound, through reacting a mal-PEG-NHS bifunctional linker with a benzazepine derivative, comprising an amine functional group, as shown below:
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In regard to the number of PEG repeats, it is taught that the linker may comprise one or more PEG repeats and also states “A linker can contain maleimides linked to polyethylene glycol molecules in which the polyethylene glycol can allow for more linker flexibility or can be used lengthen the linker” ([0474]). This teaches that number of PEG units has a measurable effect on linker flexibility/length, which in turn would justify the use of routine optimization, in order to identify the ideal polymer length for optimum flexibility.
Coburn does not teach all of the limitations of instant claim 48, specifically with regard to the structure of the benzazepine derivatives. Cooper teaches these deficiencies.
Cooper et al teach 2-aminobenzazepine derivatives, useful in the treatment of treatment of myelosuppression, including suppression associated with cancer chemotherapy, as well as activation of the immune system for the treatment of cancer (Page 1). The disclosed compounds are described by the following formula:
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A possible embodiment of the disclosed compounds is as follows:
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This embodiment teaches the limitations, regarding the structure of the benzazepine derivative, established in instant claims 48, 52, and 57.
It would have been obvious to combine the teachings of Coburn (linker-payloads comprising benzazepine derivatives) with the immune-stimulating benzazepine derivatives of Cooper. Coburn discloses linker-payloads, which comprise a benzazepine derivative covalently attached to reactive moiety (e.g. maleimide functional group) through a linker (e.g. PEG polymer), for use in the treatment of cancer/modulating TLR8 activity. The invention claimed in the current application shares an identical overall structure, with the sole exception being the structural nature of the benzazepine derivative, as that disclosed by Coburn. The simple substitution of one benzazepine derivative, possessing TLR8-agonist characteristics, with another, as in the current application, would have been obvious to one-skilled in the art at the time of filing. As suggested by Coburn, compounds, comprising a benzazepine core, were known in the prior art to exhibit TLR8-specific agonist activity ([0462]). Furthermore, 2-amino-benzazepines, such as those encompassed by the disclosure of Cooper, are known to be effective TLR8-specific agonists, as evidenced by Kieffer, which teaches that 2-amino-benzazepines, showed good selectivity towards TLR8, and were tolerant to a range of substitutions (Section 2.11). Therefore, by substituting the immune-stimulating benzazepine derivatives, disclosed by Coburn, with those taught by Cooper, one arrives at a molecule possessing properties, that would have been entirely predictable and obvious to one skilled in the art, at the time of filing.
In regard to claim 63, by combining the benzazepine derivative, encompassed by the teachings of Cooper, with the exemplary scheme for producing linker-payloads, taught by Coburn, both of which were presented above, one would arrive at a molecule embodying the limitations established in instant claim 63, as shown below.
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Claims 34 and 64 are rejected under 35 U.S.C. 103 as being unpatentable over US20180258048 A1 (herein Coburn) in view of EP 0 825 186 A1 (herein Cooper), both of which were presented in the IDS submitted on 15 April 2024, with Kieffer ME, et al. (2020) Small molecule agonists of toll-like receptors 7 and 8: a patent review 2014 - 2020. Expert Opin Ther Pat. 2020 Nov;30(11):825-845 (herein Kieffer) and Thermo Scientific Crosslinking Technical Handbook 2012 (herein Thermo), Annunziato ME, et al. (1993) p-maleimidophenyl isocyanate: a novel heterobifunctional linker for hydroxyl to thiol coupling. Bioconjug Chem. 1993 May-Jun;4(3):212-8 (herein Annunziato), and AP11476, Safety Data Sheet for Mal-amido-PEG10-acid (herein Axis) providing additional evidentiary value.
As discussed for 35 U.S.C. 103 rejections of claims 48, 52-54, 59, 61, and 63, Cooper and Coburn teach linker-payloads comprising benzazepine derivatives. Coburn teaches that the payload may be formed using various methods but only provides a small number of examples ([0570-0579]).
Coburn does not explicitly teach a method that would produce the L-Q structure found in the compound of claim 64. However, the use of a linker comprising an isocyanate functional group would yield a structure corresponding to that shown in the claim. Linkers comprising isocyanate functional groups have been a well-known class of cross-linking reagents for many years as evidenced by Thermo, which identifies isocyanate as amine-reactive chemical group, suitable for crosslinking (Table 2 and Page 3-Amine-reactive chemical groups). Further evidence of this, includes the commercial availability of various mal-PEG-NCO linkers, prior to the effective filing date of the current application, offered by companies such as Advanced BioChemicals, which marketed various mal-PEG-NCO linkers, as early as 26 August 2016 (https://web.archive.org/web/20161220031300/https://advancedbiochemicals.com/product/mal-peg-nco/). Alternatively, it should be noted that Annunziato teaches a method for converting carboxyl (CO2H) functional groups into isocyanates, through azide intermediates, which allows for an expanded library of potential linkers, as any mal-PEG-acid compound, could readily be converted to the corresponding mal-PEG-NCO compound (Scheme 2). Thus, by converting mal-amido-pPEG10-acid, a compound that was commercially available at the time of filing (see date listed in Axis), into the corresponding mal-amido-PEG10-NCO, and reacting it with the benzazepine derivative cited above, one would arrive at the compound referenced in claim 64 and 34. Furthermore, as discussed for the 35 U.S.C. 103 rejections of claims 1 and 48, Coburn teaches linker-payloads and the immunoconjugate product of the linking reaction, utilizing said linker-payloads, as a result any immunoconjugate product, resulting from a linking reaction comprising the linker-payload described above would encompass the limitations established in instant claims 12-15, 18, 26-28, 32, 35, 44, and 47.
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, 10, 12-16, 18, 26, 27, 34-39, 42, 44, 48, 52, 53, and 59 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 50, and 55-60 of U.S. Patent No. 12570610 (herein ‘610). Although the claims at issue are not identical, they are not patentably distinct from each other, because the limitations of claims 1-3, and 55-60 of ‘610 describe a group of molecules that overlap with the molecules described in instant claims 42. An example of this overlap is the fact that the following compound selected from instant claim 34 meets all the limitations established in reference claims 1, 55, 58, and 59, when the claim limitations of instant claim 42 are applied (i.e. the compound is conjugated to an antibody). Furthermore, reference claim 50 teaches the use of the described compounds for the treatment of cancers, which overlaps with the limitations of instant claims 37.
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Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MATTHEW CURRAN METCALF whose telephone number is (571)272-5520. The examiner can normally be reached 7:30AM-5:00PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama, can be reached at (571)272-2911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MATTHEW CURRAN METCALF/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
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