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 .
Specification
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
This application contained polynucleotide and/or polypeptide sequence information. Applicant is required to review the specification for compliance with the above.
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.
Claims 1-16 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.
It is unclear if “isotopic labels” refers to a isotopes of the atoms of the recited conjugates or that the conjugate is further bound to another isotope.
Claim 3 recites conjugates of formula I-1 with an unassigned stereocenter:
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Claim 3 also recites formulas Ia-1 and Ib-1 that define the R and S stereoisomers, respectively. The claim therefore recites a broad formula together with narrower formulas with chiral limitations that fall within the broader definitions of formula I-1. The rejected claims are considered indefinite because there is a question or doubt as to whether the narrower stereoisomers are merely exemplary of the claim, and therefore not required, or are required structural limitations.
Claim 16 recites broad methods without any particular process steps. Moreover, the structures of the recited linker-drugs are not defined.
The claims are replete with “preferably” language. It is unclear if the claims are to be limited to the preferred embodiments.
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.
Claims 1-6 and 8-16 are rejected under 35 U.S.C. 103 as being unpatentable over CN 113943310 as evidenced by counterpart U.S. Publication No. 20230381332 based on an application by Zhu et al. (Zhu) in view of:
Harbeson et al., Deuterium in Drug Discovery and Development in Annual Reports in Medicinal Chemistry, 2011, pp. 403-417 (Harbeson); and
WO 2020022363 as evidenced by counterpart U.S. Publication No. 20210283269 based on an application by Yamaguchi et al. (Yamaguchi).
Citations to Zhu are made with reference to U.S. Publication No. 20230381332.
Zhu teaches deuterated camptothecin derivative and its antibody-drug conjugate (ADC), and combines the deuteration technology with camptothecin ADC to discover improved deuterated camptothecin ADC drug, so that it has higher safety and efficacy and can better meet the clinical challenge.
[0004] The camptothecin family of drugs including irinotecan, eatecan, and SN38, etc., are known as antitumor small molecule compounds and inhibit DNA topoisomerase I to exhibit antitumor effects. Camptothecin drugs have been used widely in clinical practice, the main indications are bone cancer, prostate cancer, breast cancer, pancreatic cancer and so on. Unlike irinotecan, which is currently used clinically, eatecan does not require activation by utilizing enzymes. In addition, compared with SN-38, which is the pharmacodynamic body of irinotecan, and topotecan, which is also used in clinical practice, the inhibitory activity to topoisomerase I is stronger and there is more cell-wounding activity against a variety of cancer cells in vitro. In particular, it has also shown an effect on cancer cells that show resistance to SN-38 through the expression of P-glycoprotein
Zhu specifically teaches the following antibody conjugates at page 17:
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Synthesis of the ADC’s are provided in the examples.
[0160] The term “antibody” refers to immunoglobulin, a tetrapeptide structure consisting of two identical heavy chains and two identical light chains connected by interchain disulfide bonds. The amino acid composition and sequence of the heavy chain constant region of immunoglobulin are different, so its antigenicity is also different. On this basis, immunoglobulins can be divided into five classes, or isotypes of immunoglobulins, namely IgM, IgD, IgG, IgA, and IgE, with their corresponding heavy chains being μ, δ, γ, α, and ε chain. Ig can be divided into different subgroups according to the amino acid composition of hinge region and the number and location of heavy chain disulfide bonds. For example, IgG can be divided into IgG1, IgG2, IgG3, and IgG4. The light chain is divided into κ chain or λ chain through the difference of the constant region. Each of the five types of Ig can have a κ chain or a λ chain. The antibody of the invention is preferably a specific antibody against the cell surface antigen on the target cell, and the non-restrictive embodiments are…anti-EGFR antibody.
The above conjugates cover the instant “isotopic labels” of the instant conjugates, given the broadest reasonable interpretation of that term. See [0073] of the Published Application No. 20250345445: “Unless otherwise specified, the term “isotopic label” means that the compounds of the present invention can exist in isotope tagged or enriched form containing one or more atoms having an atomic mass or mass number different from the atomic mass or mass number most abundantly found in nature.”
Nonetheless, the recited non-deuterated compounds are prima facie obvious modifications of their deuterated counterparts in Zhu because replacing hydrogen with deuterium is an isotopical change but preserves the molecule's overall special arrangement and stereochemistry. Carbon-deuterium bonds have a lower zero-point vibrational energy, making them more stable and harder to break than carbon-hydrogen bonds, see Harbeson. However, most deuterated compounds reported-to-date appear to retain full biochemical potency and selectivity”, see Id, Conclusions. Therefore, those of ordinary skill would reasonably expect that the instant non-deuterated ADC’s would have similar pharmacology as the deuterated conjugates of Zhu.
Zhu may not explicitly teach the particular anti-EGFR antibody required by the claims. However, Yamaguchi discloses that the HC/LC structures of HER2 and HER3 that can be conjugated to exatecan are respectively SEQ ID NOs: 1/2 and 3/4 (totally identical to SEQ ID NOs: 9, 10, 19 and 20 of the present application) (see description, paragraphs 597-613). Yamaguchi also teaches the HV/ LV and HCDR1-3/LCDR1-3 of EGFR that can be conjugated to a drug and SEQ ID NOs: 1/2 and 5-7/12-14 (totally identical to SEQ ID NOs: 27/28 and 21-23/24-26 of the present application) (equivalent to SEQ ID NOs: 9, 10, 19, and 20 of the present application).
In this way, those of ordinary skill could have applied the anti-EGFR antibodies of Yamaguchi in the manner required and in a predictable fashion for the purposes of providing the instant ADC’s. As outlined above, Zhu teaches ADC’s with the structural requirements of the instant linker-exatecan moieties. Yamaguchi is added for the proposition that the instant anti-EGFR antibodies are applicable to these ADC’s. Specifically, Yamaguchi teaches that the particular known technique of using the instant antibodies to prepare exatecan ADC’s was recognized as part of the ordinary capabilities of one skilled in the art. In this manner, those of ordinary skill would have recognized that applying the known technique to exatecan ADC’s, such as those taught by Zhu, would have yielded predictable results. Accordingly, using the recited anti-EGFR antibodies for the purposes of preparing the instant anti-EGFR-exatecan ADC’s would have been prima facie obvious.
Claims 1-6 and 8-16 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. Publication No. 20240358843 based on an application by Huang et al. (Huang) in view of WO 2020022363 as evidenced by counterpart U.S. Publication No. 20210283269 based on an application by Yamaguchi et al. (Yamaguchi).
Huang teaches the following ADC at page 158, for cancer treatment:
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Synthesis of the ADC’s are provided in the examples.
[0095] Another aspect of the present application provides the use of the conjugate compound or the pharmaceutically acceptable salt thereof of the present application, or the pharmaceutical composition as described in the present application in the preparation of a drug for treating a disease in a subject.
[0096] In some embodiments, the disease of the present application is selected from the group of: a cancer, an immune disease, a metabolic disease, and a neurological disease. In some embodiments, the cancer is selected from pancreatic cancer, biliary tract cancer, liver cancer, breast cancer, thyroid cancer, colorectal cancer, esophagus cancer, lung cancer, kidney cancer, leukemia, ovarian cancer, stomach cancer, uterine cancer, endometrial cancer, colon cancer, testicular cancer, skin cancer, prostate cancer, lymphoma, and multiple myeloma.
Huang may not explicitly teach the particular anti-EGFR antibody required by the claims. However, Yamaguchi discloses that the HC/LC structures of HER2 and HER3 that can be conjugated to exatecan are respectively SEQ ID NOs: 1/2 and 3/4 (totally identical to SEQ ID NOs: 9, 10, 19 and 20 of the present application) (see description, paragraphs 597-613). Yamaguchi also teaches the HV/ LV and HCDR1-3/LCDR1-3 of EGFR that can be conjugated to a drug and SEQ ID NOs: 1/2 and 5-7/12-14 (totally identical to SEQ ID NOs: 27/28 and 21-23/24-26 of the present application) (equivalent to SEQ ID NOs: 9, 10, 19, and 20 of the present application).
In this way, those of ordinary skill could have applied the anti-EGFR antibodies of Yamaguchi in the manner required and in a predictable fashion for the purposes of providing the instant ADC’s. As outlined above, Huang teaches ADC’s with the structural requirements of the instant linker-exatecan moieties. Yamaguchi is added for the proposition that the instant anti-EGFR antibodies are applicable to these ADC’s. Specifically, Yamaguchi teaches that the particular known technique of using the instant antibodies to prepare exatecan ADC’s was recognized as part of the ordinary capabilities of one skilled in the art. In this manner, those of ordinary skill would have recognized that applying the known technique to exatecan ADC’s, such as those taught by Huang, would have yielded predictable results. Accordingly, using the recited anti-EGFR antibodies for the purposes of preparing the instant anti-EGFR-exatecan ADC’s would have been prima facie obvious.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Zhu or Huang in view of:
Harbeson and Yamaguchi;
in further view of: Burke et al., British Journal of Anaesthesia, Volume 88, Issue 4, 2002, Pages 563-576 (Burke).
The teachings of the primary and secondary references and their application to claim 7 is set forth above and incorporated herein by reference.
The primary and secondary references may not specifically teach the recited enantiomers required by the rejected claims.
However, Burke teaches the principles of stereochemistry and pharmacology. Burke explicitly teaches the concept of the eudysmic ratio, noting that for a given racemic drug, one enantiomer (the eutomer) typically possesses the majority of the desired pharmacological activity, while the opposite enantiomer (the distomer) is often less active, inactive, or responsible for unwanted side effects (“When comparing affinities, the enantiomer with the highest affinity is termed the ‘eutomer’ and that with the lowest affinity the ‘distomer’. The pharmacological activity of the two enantiomers can therefore be compared by calculation of the ‘eudismic ratio’. Eudismic analysis provides a powerful tool for drug design, by optimizing a series of enantiomer pairs by the comparison of the eutomers and distomers in a series of analogues.”, page 565).
Burke teaches that methods of asymmetric synthesis and resolution are routine, see pages 566+. In this manner, Burke suggests that resolving a racemic mixture into its pure enantiomers is a standard, desirable practice to improve potency and reduce toxicity.
Therefore, the motivation to isolate an isomer of the recited ADC arises from a reasonable expectation of success that one of the enantiomers would be the eutomer, thereby exhibiting enhanced potency, a better therapeutic index, or reduced side effects compared to the racemate or other enantiomers.
Isolation of individual isomers of the ADC’s would have been obvious since stereochemical resolution of a known racemate of ADC’s represents optimization of routine variables, i.e., the different enantiomers. The selection of the most preferred enantiomer from the known racemate is nothing more than the result of testing a small, predictable number of options (the known enantiomers) with a reasonable expectation that one of the enantiomers would provide preferred properties.
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 1-16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of copending Application No. 19451100.
Although the claims at issue are not identical, they are not patentably distinct from each other.
Specifically, the conjugates covered in the conflicting claims anticipate those covered in the rejected claims. Alternatively, the difference between the conjugates covered in the conflicting claims and those covered in the rejected claims is that the conflicting claims may not recite the instant conjugates with particularity so as to amount to anticipation (See M.P.E.P. § 2131: "[t]he identical invention must be shown in as complete detail as is contained in the ... claim." Richardson v. Suzuki Motor Co., 868 F.2d 1226, 1236, 9 USPQ2d 1913, 1920 (Fed. Cir. 1989). The elements must be arranged as required by the claim, but this is not an ipsissimis verbis test, i.e., identity of terminology is not required. In re Bond, 910 F.2d 831, 15 USPQ2d 1566 (Fed. Cir. 1990).). However, the conflicting claims recite the structural elements of the instant conjugates, as well as the instant methods of making and using, with sufficient guidance, particularity, and with a reasonable expectation of success, that the invention would be prima facie obvious to one of ordinary skill (the prior art reference teaches or suggests all the claim limitations with a reasonable expectation of success. See M.P.E.P. § 2143).
Also, with regard to the instant methods of treating, the specification of Application No. 19451100 discloses the utility of the recited conjugates as covered by the instant methods of using the conjugates, see Sun Pharmaceutical Industries, Ltd., v. Eli Lilly and Co. where the district court ruled that the claims of the ‘826 patent were invalid in light of the ‘614 patent which disclosed gemcitabine’s use in cancer treatment, but did not claim it. In making this ruling, the district court relied on the Federal Circuit’s earlier rulings on double patenting of compound claims, mainly Geneva Pharmaceuticals, Inc, v. GlaxoSmithKline PLC, 349 F. 3d 1373 (Fed. Cir. 2003), and Pfizer, Inc. v. Teva Pharmaceuticals USA, Inc., 518 F.3d 1353 (Fed. Cir. 2008). In both of these cases, the Federal Circuit found claims of a later patent invalid for obviousness-type double patenting where an earlier patent claimed a compound, disclosing its utility in the specification, and a later patent claimed a method of using the compound for a use described in the specification of the earlier patent. The cases also established that in determining the scope of compound claims for a double patenting rejection one must look to the specification to interpret the utility of the compound.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KARL J PUTTLITZ whose telephone number is (571)272-0645. The examiner can normally be reached on Monday to Friday from 9 a.m. to 5 p.m.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Gregory Emch, can be reached at telephone number 571-272-8149. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KARL J PUTTLITZ/ Primary Examiner, Art Unit 1646
Prosecution Insights