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 .
Response to Amendment
The preliminary amendment filed 01/09/2024 is acknowledged. Claims 1-70 are canceled and claims 71-82 are new. No restriction is being imposed in this case. Claims 71-82 are under examination.
Effective Filing Date
Applicant’s claim for the domestic benefit of prior-filed applications under 35 U.S.C. 119(e), 121 and 365(c) is acknowledged. No foreign priority claims are made Under the AIA , the effective filing date of a claimed invention is the earlier of:
The actual filing date of the application;
OR
The filing date to which the application is entitled to a right of foreign priority or domestic benefit as to such claimed invention.
Regarding claiming domestic benefit of prior-filed applications, MPEP 211.05 sets forth the disclosure requirements, noting that “disclosure of the prior-filed application must provide adequate support and enablement for the claimed subject matter of the later-filed application in compliance with the requirements of 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph”.
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Based on the information given by Applicant and an inspection of the prior patent and applications, the examiner has concluded that the subject matter defined in the instant claims is supported by at least the disclosure in provisional application serial no. 62/274,572. The recited sequences are not disclosed in provisional application serial no. 62/254,278. Therefore, the effective filing date of the instant claims is 01/04/2016.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Interpretation
Claim 71 defines “STn” as “(α2,6)N-acetylgalactosamine”. The specification also defines it as “sialyl Tn” (see paragraph [0005]), thus both terms are used herein.
Claim 76 recites selecting a subject with cancer for treatment, which reads on a mental step. Nevertheless, the sample is contacted with the encompassed antibodies, which were not routine or conventional in the art at the time of the filing of the invention, thus the judicial exception is integrated into a practical application.
Claim Rejections - 35 USC § 112(a)
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 75 and 77-81 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for methods of treating cancers that express sialyl Tn antigen (STn) with the recited antibodies as well as the antibody drug conjugates that are conjugated to a cytotoxic agent, does not reasonably provide enablement for methods of treating cancers that do not express STn or methods of treating cancers that express STn with the recited antibodies that are not linked to either a cytotoxic agent. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use the invention commensurate in scope with these claims.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.” (See In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 Fed. Cir. 1988) These factors include, but are not limited to: (a) the breadth of the claims; (b) the nature of the invention; (c) the state of the prior art; (d) the level of one of ordinary skill; (e) the level of predictability in the art; (f) the amount of direction provided by the inventor; (g) the existence of working examples; and (h) the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The instant specification discloses antibodies comprising heavy chain variable regions (VH) and light chain variable regions (VL) that are humanized variants of the mouse “5G2-1B3” anti-sialyl(α2,6)N-acetylgalactosamine (STn) antibody. The instant specification discloses the 5G2-1B3 variable domain pairs expressed and tested initially were: SEQ ID NOs: 217/220; SEQ ID NOs: 218/221; SEQ ID NOs: 218/222; SEQ ID NOs: 219/221; SEQ ID NOs: 219/222 and SEQ ID NOs: 218/223 (see paragraph [00614]). According to Table 20 of the instant specification, which records the characterization results of the antibodies, the following 5G2-1B3 anti-STn antibodies were capable of binding to cell-associated STn: SEQ ID NOs: 218/222; SEQ ID NOs: 218/223; SEQ ID NOs: 219/222; SEQ ID NOs: 219/221 and SEQ ID NOs: 218/221 (though the instantly claimed antibodies could not be evaluated for binding to bovine submaxillary mucin-associated STn; see p. 211, Table 20). Given that there is a high degree of homology between each of the heavy variable domains and each of the light variable domains, the claims are enabled for the 15 embodiments that bind STn recited in claim 71.
The claims, however, are broad with respect to the cancer that can be treated with the encompassed 5G2-IB3 antibodies. Applicant is broadly claiming not only treatment of STn-expressing cancers, but any cancer irrespective of its expression of the target antigen. In addition, claim 75 recites methods of treatment in which the anti-STn antibody does not comprise a component that can mediate cytotoxicity against the target cancer cell even if that cell expresses STn. For cancer antigen-based therapy, expression of the antigen on at least some proportion of the cells in a tumor was generally required before an antibody to that antigen could have a therapeutic effect. For example, Loureiro et al. (Biomolecules (2015) 5:1783-1809) teach that “the target antigen of therapeutic antibodies should be expressed on the surface of the cancer cells and be abundant and accessible” (see p. 1793, last paragraph). While many epithelial cancers may express STn, the expression varies between patients and even among the same type of cancer (see J. Munkley, Int. J. Mol. Sci. 2016, 17, 275; doi:10.3390/ijms17030275, p. 1, 2nd paragraph and point 5 of pages 3-5). Munkley discloses that failure to select for patients that had a tumor expressing STn may explain the failure of the Theratope anti-STn vaccine trial (see p. 4, 3rd full paragraph). Thus, the skilled artisan understood that expression of the antigen on the tumor was required for the effectiveness of an antibody therapy targeting the tumor antigen. Accordingly, it was highly unpredictable that an antibody would have an anti-tumor effect when the tumor lacked expression of the target antigen.
Further, antibodies can mediate anti-tumor effects by several different mechanisms, for instance, by conjugating the antibody to a cytotoxic agent (an antibody-drug conjugate, or “ADC”), which kills the tumor cell by a direct effect mediated by the attached drug (see Reichert & Valge-Archer, Nat. Rev. Drug Disc. (2007) 6: 349-356, especially p. 350 under “Modes of action” and right column). Antibodies can also mediate cell killing in an “unmodified” form by activating the immune system, either via antibody-dependent cell cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), or direct induction of apoptosis. Nevertheless, not all antibodies have these activities, and ADCC and CDC both depend on the antibody isotype, which is determined by a portion of the antibody distinct from the VH and VL domains (see Reichert, p. 351, all three columns under “Immune system activation”). As discussed above, the skilled artisan understood that not all antibodies to a cancer antigen could mediate killing of a cancer cell, even if the cancer cell expressed the antigen for the antibody. Killing mediated by an antibody linked to a cytotoxic compound generally requires that the antibody be internalized. Killing via immune system stimulation such as ADCC and CDC requires an antibody of a particular isotype. Accordingly, the art recognized that antibody-based killing of tumor cells generally required expression of the target antigen on the tumor and that the antibody either be conjugated to a cytotoxic agent or be of an isotype that could mediate ADCC or CDC. The IC50 value for the parental anti-STn antibody “5G2-1B3” was shown to be “least effective”, perhaps “due to a lower DAR [drug antibody ratio] and different IgG isotype (5G2-1B3 is IgG1, whereas others are IgG2a)”, though the conjugated 5G2-1B3 killed SNU-16 cells (cancer cell line—see paragraphs [0596]-[0600] and Tables 16-17 of the DeSander PGPUB, US2016/0130356).
The specification describes humanization of the mouse 5G2-1B3 antibody (among others) and comprise VH variations as set forth in SEQ ID NOs: 220-224 and VL variations as set forth in SEQ ID NOs: 217-219 and expressed with a human IgG1 (see p. 206, Table 18, p. 210, paragraph [00618]). Antibody-drug conjugates were prepared with certain of the humanized 5G12-1B3 variants linked to MMAE and these also bound STn (see Example 9 at paragraphs [00626]-[00629] and Table 22). The additional studies are described prophetically. The post-filing date publication by Eavarone et al., (PLoS ONE (2018)13(7):e0201314 reports that “5G2-1B3 variants demonstrated low level binding to non-sialylated Tn”, thus another antibody was chosen for further development (see p. 6, under “Characterization of humanized mAbs”).
In view of the above, one of skill in the art would be required to perform undue experimentation in order to determine which, if any, cancers not expressing STn could be effectively treated with an anti-STn antibody, whether or not the antibody was conjugated to a cytotoxic drug. Further, one of skill in the art would be required to perform undue experimentation to develop variants of the claimed humanized antibodies that lacked an Fc with cytotoxic (ADCC/CDC) activity or a conjugated cytotoxic drug but could still mediate killing of STn-expressing cancer cells. For these reasons, the claims are not commensurate in scope with the enablement provided in the specification.
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 71-82 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 11,253,609 in view of Hudis (N. Engl. J. Med. 2007, 357, 39-51). Although the claims at issue are not identical, they are not patentably distinct from each other because each of the claim sets are drawn to methods of treating cancer and antibody-drug conjugates comprising anti-sialyl Tn antigen antibody. Specifically, the claims of the reference patent recite a method of treating platinum refractory cancer comprising administering to a subject with platinum refractory cancer an antibody-drug conjugate, wherein the antibody-drug conjugate comprises an antibody that binds sialyl Tn antigen (STn) conjugated to a cytotoxic agent, wherein the antibody comprises (a) a heavy chain variable domain (VH) comprising the amino acid sequence of a VH comprising the amino acid sequence of SEQ ID NO: 9, which shares 100% sequence identity to instant SEQ ID NO: 222 and a VL comprising the amino acid sequence of SEQ ID NO: 10, which shares 100% sequence identity to instant SEQ ID NO: 218. The claims of reference patent also contemplate that the cytotoxic agent is monomethyl auristatin E (MMAE).
The differences between the claim sets are as follows. In addition to methods of treatment, the instant claims are also drawn to the antibody and antibody conjugate itself, however, since the claims of the reference patent recite treatment of cancer with the same agent, it follows therefrom they were in possession of the instantly claimed antibody. Second, although the claims of the reference patent do not recite the effect of killing an STn-expressing cell, they do recite administering the anti-STn antibody to a subject in need thereof, thus any effect on an STn-expressing cell would be inherent. Third, although the claims of the reference patent do not disclose a method of making an antibody-drug conjugate as recited in instant claim 82, they teach the same antibody-MMAE conjugate, therefore, the method of making the same compound is inherent.
Regarding claim 76, it would have been obvious to one having ordinary skill in the art at the time of the filing of the invention to select a subject with cancer for treatment with an anti-STn antibody comprising contacting a sample from the subject with an anti-STn antibody because Hudis teaches that it is important to pre-select patients who are positive for the antigen targeted when treating with the antigen-targeting antibody, in that case the HER2 antibody, trastusumab (see abstract; p. 40, left column, 1st two paragraphs; p. 42, left column, last paragraph; p. 44, right column, last full paragraph). The person of ordinary skill in the art would have been motivated to pre-select patients that express the cancer antigen because it was known that monoclonal antibody treatment is only effective in disease in which the cancer antigen is expressed. See, for instance, Hudis, who teach “in a trial of patients with metastatic breast cancer and normal HER2 expression who were randomly assigned to receive paclitaxel alone or in combination with trastuzumab, no benefit from the addition of the antibody was shown. Furthermore, the person of ordinary skill in the art could have reasonably expected success because patients who showed strong expression of cancer antigen expression had the best results (see Hudis, p. 44, right column, last full paragraph).
In summary, the instant claims are not patentably distinct from those of the reference patent.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTINA M BORGEEST whose telephone number is (571)272-4482. The examiner can normally be reached M-F 9-5:30 EDT.
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/CHRISTINA M BORGEEST/Primary Examiner, Art Unit 1675