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 .
Claim Status
Claims 1 and 32-36 are cancelled. Claims 2-31 as filed on 16 November 2023 are pending and under examination.
Nucleotide and/or Amino Acid Sequence Disclosures
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.
Specific deficiencies and the required response to this Office Action are as follows:
Claim 8 has the SEQ ID NO: 7. This sequence is three amino acids in length which is a skipped sequence under ST26. The amino acids WAS are sufficient for the claim, but SEQ ID NO: 7 should be deleted from the claim.
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 8-14 and 28 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.
Claim 8 recites “WAS (SEQ ID NO:7)”, SEQ ID NO: 7 is a skipped sequence in the sequence file. It is therefore unclear what limitation the parenthetical would make as recited in claim 8.
Claims 8-14 recites the limitation "the antibody" in line 2. There is insufficient antecedent basis for this limitation in the claim or claim 2 from which it depends as there is the antibody in the antibody in the ADC, the anti-PD-1 antibodies, or anti-PD-L1 antibodies recited in claim 2 and it is unclear which antibody is being referred to.
For the purpose of examination claims 8-11 and 14 were examined to be referring to the antibody in the ADC as the sequences recited are for the antibodies that bind HER2.
For the purpose of examination 10 and 12-13 “the antibody” was examined to refer to the PD-1 or PD-L1 immune checkpoint antibody of claim 2.
Claim 28 recites the limitation "the medicament" in line 2. There is insufficient antecedent basis for this limitation in the claim or in claim 2 from which the claim depends.
For the purpose of examination the claim was read to recite “. . . wherein the ADC and immune checkpoint inhibitor are administered . . .”.
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 2-7, 10, 12-13, and 15-31 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 claim(s) contains 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 inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or it may be satisfied by the disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. “Functional” terminology may be used “when the art has established a correlation between structure and function” 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 one has invented a genus and not just a species. Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 598 F3d 1336, 94 USPQ2d 1161, 1171 (Fed Cir. 2010).
Scope of the Claimed Genus
Claim 2 is to a method of treatment comprising an ADC that comprises an antibody and MMAE. The antibody of the ADC is defined as biding HER2 and comprising the heavy chain CDRs or the light chain CDRs of distamab vedotin.
Claims 3-7, 10, 12-13, and 15-31 do not provide further limitations on the antibody of the ADC.
Summary of Species Disclosed in the original specification
The applicant discloses one HER2 binding antibody comprising the CDRs of disitamab. The HCDR 1, 2, and 3 of instant SEQ ID NO: 3, 4, and 5 with LCDR 1, 2, and 3 of SEQ ID NO: 6,7, and 8; and HCDR 1, 2, and 3 of SEQ ID NO: 31, 32, and 33, with LCDR 1, 2, and 3 of SEQ ID NO: 34, 35, and 8 where the CDRs vary based on antibody numbering scheme used with the VH and VL of SEQ ID NO: 9 and 10, respectively.
State of the Relevant Art
Human Epidermal Growth Factor Receptors are known to be associated with multiple cancers including urothelial cancer and are related to cell growth, proliferation, and possibly chemotherapy resistance Koshkin et al. Bladder Cancer. 5(1):1-12. (2019) (PTO-892) (abstract and page 2 in col 1 in par 1). HER2 is known to generate downstream activation signaling pathways without a ligand (page 2 in col 1 in par 1). HER2 is known to be a biomarker for cancer, but targeting of HER2 for treatment of cancer is inconsistent (page 2 in col 1 in par 2 and col 2 in lines 1-11).
It has been established for decades in the art that the formation of an intact antigen-binding site in a conventional antibody requires the association of the complete heavy and light chain variable regions of a given antibody, each of which comprises three CDRs (or hypervariable regions) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro et. al., Front. Immunol. 2018; 8:1751 (PTO-892) (see Section “The IgG Molecule” in paragraph 1 and Figure 1). While affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (page 3 “The IgG Molecule”, second and third paragraphs), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori. E.g., id., (page 6 ending paragraph onto page 7).
Brown et al., J. Immunol., 156(9):3285-91 (1996) (PTO-892), teaches that although a single amino acid change in CDR2 of heavy chain of a particular antibody was tolerated, the antibody lost binding upon introduction of two amino acid changes in the same region. Brown, p. 3290 and Tables 1 and 2. Table 1 of Brown shows that even a conservative substitution does not ensure that functionality of the antibody is retained. The older citation is supported by more recent discoveries of why these substitutions change antibody activity. Marvin et. al., Biochemistry, 42(23):7077-7083 (2003) (“Marvin” PTO-892) teaches that changes to the heavy and light chains altered binding affinity (Table 2) with changes to the CDR having large impacts but the changes with the largest impact were from residues in the CDR, but not from ones interfacing with the antigen ( Page 7081 in col 1 “Conclusions and Discussion” and Page 7082 in Figure 4).
This is confirmed by Chiu et al., Antibodies, 8(55):1-80. (2019) (“Chiu” PTO-892). Chiu teaches that the complementarity-determining regions (HCDRs 1-3 and LCDRs 1-3) determine antigen binding requiring specific sequences and orientation of those sequences to properly form tertiary structures that can recognize and bind antigens (Page 4 in 1.2.2 first and last paragraphs and Figure 3). Chiu teaches that antibody modeling with known LCDRs 1-3, HCDR1 and HCDR2 could not predict HCDR3. Structure-Based antibody engineering is unable to predict antibody sequences (Page 6 in 1.2.6, Pages 10-11 in Section 2 in particular second paragraph of page 11). Chiu notes the advancement in antibody engineering but notes it is still not possible to predict the point mutations that would improve affinity in both antibodies and multispecific molecules (Page 51 in lines 6-12). Chiu teaches that antibody-drug conjugates (ADCs) comprise antibodies that act as binding domains and that being in an ADC does not change the binding expectations of the antibody within the ADC (page 32 in Section 3.3 in particular par 1 and 4).
In general, absent at least the conserved structure of the CDRs of the heavy chain and light chain of an antibody, the skilled artisan generally would not be able to visualize or otherwise predict an antibody with a particular set of functional properties would look like structurally.
Are the disclosed species representative of the claimed genus?
MPEP § 2163 states that 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.
The specification discloses 2 CDR sets but only a single HER2 binding antibody.
Given the variability encompassed by the genus of HER2 binding antibodies with only the CDRs of the light or heavy chain defined the described species therefore cannot be considered representative of the genus. An antibody as defined by its CDRs provides only the binding activity of that antibody not of any variation to those sequences.
Identifying characteristics and structure/function correlation
In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics; i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. To meet this requirement in the instant case, the specification must describe structural features that the skilled artisan as of the effective filing date would have expected to convey the claimed binding activity.
As noted above, the art identifies the CDRs of an antibody as the structure that
provides its function. A single change to an amino acid in one CDR changes its binding
activity. The disclosure provides only a single structure with a known function. The claims are to antibodies based on only their function of binding HER2 with only partial definition of the CDRs where only the heavy or light chain are defined. The heavy chain CDRs of the claims do not inform the structure of the light chain CDRs and are not sufficient to provide the required activity of binding HER2. The same is true for the light chain CDRs as they would not inform one of skill in the art the structure of the heavy chain and do not provide the function of binding HER2. The disclosed species only provides the function of that disclosed set of six CDRs.
Conclusion:
The claims only define either the heavy chain CDRs or light chain CDRs allowing for variation in half of the six CDRs that provide the binding activity of an antibody.
For all of the reasons presented above, one of skill in the art would not know which combinations of heavy chain CDRs would bind HER2 with the defined light chain CDRs or which combinations of light chain CDRs would bind HER2 with the defined heavy chain CDRs. The disclosure in view of the antibody art does not provide guidance on what CDR sequences would bind HER2 besides the defined sequences of instant claims 8-9.
Therefore, the skilled artisan would not reasonably conclude that the inventors had full possession of the antibodies as broadly claimed at the time the application was filed. Given the lack of shared structural properties that provide the claimed binding activity, the limited number of species described, and the fact that the species that were described cannot be considered representative of the broad genus, Applicant was not in possession of the invention as claimed.
Examiner notes claims 8-9, 11, and 14 are not included in this rejection as they have fully defined CDRs of the heavy and light variable chains.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 2, 8-10, 12-13, 15, 18-19, 22-27, and 31 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by NCT04264936 (“Clinical Trial” PTO-892) (Published 02-13-2020), as evidenced Tang et al. Journal of Hematology & Oncology. 12(7):1-15 2019. (PTO-892), FDA. Oncology Times. 42(20):37-38. (2020) (PTO-892), and Wenshe (US 20220402998 A1) (PTO-892).
Clinical Trial teaches RC48-ADC where the ADC is linked to MMAE and JS001 in a method of treating urothelial cancer (page 6 in par 1 and page 7 in Assigned Interventions). JS001 is an anti-PD1 antibody also known as toripalimab as evidenced by Tang (page 2 in col 2 in par 2). Disimitab vedotin of the claims comprises the antibody RC48 as evidenced by FDA (page 38 in col 1 in par 2).
Regarding claims 8-9, the HCDR 1, 2, and 3 with LCDR 1, 2, and 3 of the claim are the CDRs of RC48 meaning Clinical Trial teaches the requirement of the claims by teaching RC48.
Regarding claims 10 and 12-13, JS001 is a humanized IgG4 monoclonal antibody thus Clinical Trial inherently teaches the requirement of these claims as evidenced by Tang (Abstract).
Regarding claim 11, RC48-ADC comprises the VH of instant SEQ ID NO: 9 and the VL of SEQ ID NO: 10, as evidenced by Wenshe as Wenshe teaches disitamab of SEQ ID NO: 236 and 237 of the heavy chain and light chain, respectively, which match instant SEQ ID NO: 9 and 10.
Regarding claims 22-27, Clinical Trial teaches the inclusion criteria as patients with locally advanced or metastatic malignant urothelial carcinoma who are cisplatin ineligible, this would include patients who cannot tolerate platinum-based chemotherapy, or progressed after at least one line standard systemic chemotherapy. Clinical Trial further teaches patients that have progression within 12 months of neo adjuvant therapy (page 9 in “Criteria”).
Regarding claim 31, Clinical Trial teaches all of the active method steps of instant claims 2 and 31 in the same patient population and would therefore inherently have the outcome of progression-free survival of greater than 7.5 months.
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 2-6 are rejected under 35 U.S.C. 103 as being unpatentable over NCT04264936 (“Clinical Trial” PTO-892) (Published 02-13-2020) and Koshkin et al. Bladder Cancer. 5(1):1-12. (2019) (PTO-892), as evidenced Tang et al. Journal of Hematology & Oncology. 12(7):1-15 2019. (PTO-892) and FDA. Oncology Times. 42(20):37-38. (2020) (PTO-892).
Clinical Trial teaches RC48-ADC where the ADC is linked to MMAE and JS001 in a method of treating urothelial cancer (page 6 in par 1 and page 7 in Assigned Interventions). JS001 is an anti-PD1 antibody also known as toripalimab as evidenced by Tang (page 2 in col 2 in par 2). Disimitab vedotin of the claims comprises the antibody RC48 as evidenced by FDA (page 38 in col 1 in par 2).
Clinical trial teaches the use of a HER2 binding ADC and a PD-1 binding antibody for use in the treatment of urothelial cancer.
Clinical trial does not teach the urothelial cancer is HER2+, it also does not teach the detection of HER2 by IHC assay or the expression level of HER2 being 2+ or 3+.
These deficiencies are filled by Koshkin.
Koshkin teaches targeting HER2 in multiple cancers including breast, gastroesophageal, and urothelial cancer (Abstract). Koshkin further teaches HER2 expression with higher response rate and median survival in clinical trials that confirmed HER2 expression and with 2+ and 3+ IHC for HER2 expression (Table 1 and page 2 in col 2 in lines 5-10).
It would have been obvious at the time the application was filed to combine the method of treating urothelial cancer of Clinical Trial which comprises the use of a HER2 binding ADC and a PD-1 binding antibody with IHC testing for HER2 expression at +2 or +3 expression of HER2 as taught by Koshkin. One of skill in the art would have been motivated by the knowledge that HER2 binding by the ADC requires HER2 expression on the urothelial cancer being treated and the higher response rate and median survival with +2 and +3 expressing cancer taught in Koshkin. There would have been a reasonable expectation of success as Koshkin teaches IHC of urothelial cancer for HER2 and increased clinical outcomes with patients with confirmed higher expression of HER2 for therapeutics that target HER2.
Claims 2, 14, and 28-30 are rejected under 35 U.S.C. 103 as being unpatentable over NCT04264936 (“Clinical Trial” PTO-892) (Published 02-13-2020), Wenshe (US 20220402998 A1) (PTO-892), and Fang (WO 2015074528 A1) (IDS), as evidenced by Tang et al. Journal of Hematology & Oncology. 12(7):1-15 2019. (PTO-892), FDA. Oncology Times. 42(20):37-38. (2020) (PTO-892), and Wenshe (US 20220402998 A1) (PTO-892).
Claim 14 requires the heavy chain of instant SEQ ID NO: 1 which comprise the VH of instant SEQ ID NO: 9 and the constant domain of human IgG1 and light chain of instant SEQ ID NO: 2 which comprise the VL of instant SEQ ID NO: 10 with the IgG1 kappa light constant domain.
The teachings of Clinical Trial from the previous rejections under 35 U.S.C. 102 and 103 are incorporated here in full.
Clinical Trial teaches RC48-ADC where the ADC is linked to MMAE and JS001 in a method of treating urothelial cancer (page 6 in par 1 and page 7 in Assigned Interventions). JS001 is an anti-PD1 antibody also known as toripalimab as evidenced by Tang (page 2 in col 2 in par 2). Disimitab vedotin of the claims comprises the antibody RC48 as evidenced by FDA (page 38 in col 1 in par 2).
Clinical trial teaches the use of a HER2 binding ADC and a PD-1 binding antibody that would act as an immune checkpoint inhibitor for use in the treatment of urothelial cancer.
The teachings of Wenshe from the previous rejection under 35 U.S.C. 102 are incorporated here in full.
Clinical Trial and Wenshe teaches the ADC of the method of Clinical Trial comprises the VH and VL of SEQ ID NO: 9 and 10 as previously described.
Clinical Trial evidenced by Wenshe does not teach the human IgG1 and light kappa domains as required by instant SEQ ID NO: 1 and 2 and does not teach the ADC doses of 1.5 mg/Kg or administration every 2 weeks or 14 days. Further, Clinical Trial in view of Wenshe does not teach the intravenous administration of the ADC of RC48 with MMAE.
These deficiencies are filled by Fang.
Regarding claim 14, Fang teaches anti-HER2 antibodies and the antibodies as ADCs for treatment of tumors (abstract). Fan further teaches RC48 the specific anti-HER2 antibody of the claims and of Clinical Trials and Wenshe (Figure 3). Fang teaches an ADC comprising RC48 and MMAE (Table 6). Fang taches the ADC comprises IgG1 and kappa light domains (page 5 in final line, page 8 in par 11, page 9 in Example 2 in pars 2-3 and page 10 in pars 3 and 5).
Regarding claim 28, Fang teaches the intravenous administration of RC28-MMAE (page 13 in lines 7-8).
Regarding claims 29-30, Fang teaches the administration of 1.5 mg/kg of RC48-MMAE ADC that inhibited tumor growth (page 12 in par 16) Fang teaches administration on multiple schedules including every 2 weeks (page 11 in line 2).
It would have been obvious at the time the application was filed to substitute the generic constant regions of the RC48 in the ADC of Clinical Trial evidenced by Wenshe with the human IgG1 and light kappa constant regions of Fang to produce an ADC comprising RC48 with the sequences of instant SEQ ID NO: 1 and 2 with MMAE. The substitution would be prima facie obvious as they are art equivalents that have the same biological activity as constant regions of antibodies (MPEP 2144.09, 2144.00, and 2144.08). Further, Fang explicitly teaches the ADC of RC48 with MMAE taught by Clinical Trial for use in treatment of cancer.
Regarding the dose of 1.5 mg/kg and administration ever 2 weeks, it would have been obvious to combine the method of treatment taught by Clinical Trial in view of Wenshe with the dose, schedule, and intravenous administration of Fang. Fang specifically teaches dose and schedule for the same ADC of Clinical Trial and Wenshe. One of skill in the art would have been motivated to use art known doses for the ADC of Clinical Trial. There would have been a reasonable expectation of success as Clinical Trial, Wenshe, and Fang all teach the same ADC for use in cancer.
In regards to the specific dosage and interval amounts recited in the instant claims "[w]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955), and see M.P.E.P. § 2144.05 II.A. Moreover, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). This because, as is made clear from the prior art, the determination of the dosage regimen of a known drug is well within the purview of one of ordinary skill in the art at the time the invention was made, and it would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal intervals of treatment because optimal intervals is an art-recognized result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. Therefore, it would be conventional and within the skill of the art to identify the optimal dosages administered and optimal intervals to achieve target levels and therapeutically effective doses. Further, it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. It is clear that both the prior art and claimed method perform the same protocol to achieve the same results. It would be conventional and within the skill of the art to determine the optimal treatment regimens. Accordingly, one can see that the courts, over a period of over 50 years, have consistently held that treatment (ie dosage and intervals) optimization is obvious.
Claims 2, 12-13, and 20-21 are rejected under 35 U.S.C. 103 as being unpatentable over NCT04264936 (“Clinical Trial” PTO-892) (Published 02-13-2020) and Vandeveer et. al. Cancer Immunol Res. 4(5):452-462. (2016) (PTO-892), as evidenced Tang et al. Journal of Hematology & Oncology. 12(7):1-15 2019. (PTO-892) and FDA. Oncology Times. 42(20):37-38. (2020) (PTO-892).
Clinical Trial teaches RC48-ADC where the ADC is linked to MMAE and JS001 in a method of treating urothelial cancer (page 6 in par 1 and page 7 in Assigned Interventions). JS001 is an anti-PD1 antibody also known as toripalimab as evidenced by Tang (page 2 in col 2 in par 2). Disimitab vedotin of the claims comprises the antibody RC48 as evidenced by FDA (page 38 in col 1 in par 2).
Clinical trial teaches the use of a HER2 binding ADC and a PD-1 binding antibody that would act as an immune checkpoint inhibitor for use in the treatment of urothelial cancer.
Clinical Trial does not teach the use of the immune checkpoint inhibitor avelumab, an anti-PD-L1 antibody.
This deficiency is filled by Vandeveer.
Vandeveer teaches the use of the immune checkpoint inhibitor avelumab that binds PD-L1 for treatment in bladder tumors to interrupt PD-1/PD-L1 signaling in cancer (abstract).
Regarding claims 12-13, Vandeveer teaches avelumab is a human IgG1 antibody that interacts with PD-L1 and interrupts its signaling (page 454 in col 2 in par 3). Vandeveer teaches success treatment of cancer using avelumab alone (Figure 2).
It would have been obvious at the time the application to substitute the immune checkpoint inhibitor JS001 of the method of treating urothelial cancer of Clinical Trial that comprises the use of a HER2 binding ADC and a PD-1 binding antibody with the immune checkpoint inhibitor of avelumab taught by Vandeveer. The substitution would be prima facie obvious as JS001 and avelumab are art equivalents that have the same biological activity of inhibiting PD-1/PD-L1 activity in tumors (MPEP 2144.09, 2144.00, and 2144.08). Further, Vandeveer teaches bladder cancer as PD-L1 positive, which avelumab binds. There would have been a reasonable expectation of success as Clinical Trial and Vandeveer both teach immune checkpoint inhibitors for use in treating cancer.
Claims 2 and 16-17 are rejected under 35 U.S.C. 103 as being unpatentable over NCT04264936 (“Clinical Trial” PTO-892) (Published 02-13-2020) and Tang et al. Scientific Reports. 7:1-10. (2017) ( “Tang Y”PTO-892), as evidenced Tang et al. Journal of Hematology & Oncology. 12(7):1-15 2019. (PTO-892) and FDA. Oncology Times. 42(20):37-38. (2020) (PTO-892).
Clinical Trial teaches RC48-ADC where the ADC is linked to MMAE and JS001 in a method of treating urothelial cancer (page 6 in par 1 and page 7 in Assigned Interventions). JS001 is an anti-PD1 antibody also known as toripalimab as evidenced by Tang (page 2 in col 2 in par 2). Disimitab vedotin of the claims comprises the antibody RC48 as evidenced by FDA (page 38 in col 1 in par 2).
Clinical trial teaches the use of a HER2 binding ADC and a PD-1 binding antibody that would act as an immune checkpoint inhibitor for use in the treatment of urothelial cancer.
Clinical Trial does not teach the Drug to Antibody-ratio (DAR) for the HER2 binding ADC.
This deficiency is filled by Tang Y.
Tang Y teaches DAR of ADCs is important for therapeutic efficacy and pharmacokinetics (Abstract). Tang Y teaches most ADC drug candidates have their DAR maintained at about 2-4, which matches the 2-7 of instant claim 16, and 3.5 to 4.5 of instant claim 17 (page 1 in par 2). The ADCs of Tang Y include ones comprising MMAE (Figure 1).
It would have been obvious at the time the application was filed to combine the method of treating urothelial cancer of Clinical Trial that comprises the use of a HER2 binding ADC and a PD-1 binding antibody with the DAR of about 2-4 of Tang Y as a starting dose. One of skill in the art would have been motivated to use commonly known to be effective DAR that is taught by art which Tang Y provides. There would have been a reasonable expectation of success as Tang Y provides art tested and known DAR for use in treatment of patients.
In regards to the specific dosage, in this case DAR, recited in the instant claims "[w]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955), and see M.P.E.P. § 2144.05 II.A. Moreover, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). This because, as is made clear from the prior art, the determination of the dosage regimen of a known drug is well within the purview of one of ordinary skill in the art at the time the invention was made, and it would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal DAR as DAR is an art-recognized result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. Therefore, it would be conventional and within the skill of the art to identify the optimal DAR administered to achieve target levels and therapeutically effective doses. Further, it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. It is clear that both the prior art and claimed method perform the same protocol to achieve the same results. It would be conventional and within the skill of the art to determine the optimal treatment regimens. Accordingly, one can see that the courts, over a period of over 50 years, have consistently held that treatment (ie DAR) optimization is obvious.
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 2-6, 8-15, 18-19, and 22-31 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-109 of copending Application No. 19564737 (Reference Application) in view of NCT04264936 (“Clinical Trial” PTO-892) (Published 02-13-2020).
Regarding claims 2, 8-9, 11-13,15, and 18, the reference application recites the ADC of the instant claims by reciting a HER2 binding ADC of MMAE and an antibody where the heavy and light chains are SEQ ID NO: 9 and 11 which match instant SEQ ID NO: 1 and 2 thus teaching an ADC comprising the antibody of the sequences of instant claims 2, 8-9, 11, and 14 (claims 4-5). The reference application recites the drug is MMAE (claim 8) and the method comprising a PD-1 antibody (claims 1 and 16). The sequences of SEQ ID NO: 9 and 11 teach human IgG1 meeting the requirements of instant claims 12-13.
Regarding claims 3-6, the reference application recites the IHC detection of HER2 of +2 and +3 (claims 30-33).
Regarding claim 19, the reference application recites toripalimab (claim 16).
Regarding claims 22-24, the reference application recites unresectable locally advanced cancer where the patient has previously received chemotherapy (claim 36).
Regarding claim 28, the reference application recites intravenous administration (claim 54).
Regarding claims 29-30, the reference recites administration of the ADC at a dose of 2.0 mg/kg ever 2 weeks (claims 38-49 and 56).
Regarding claim 31, the reference application recites a PFS of greater than 7.5 months (claim 53).
The reference application does not recite the treatment of urothelial carcinoma.
This deficiency is filled by Clinical Trial.
Clinical Trial teaches RC48-ADC where the ADC is linked to MMAE and JS001 in a method of treating urothelial cancer (page 6 in par 1 and page 7 in Assigned Interventions). JS001 is an anti-PD1 antibody also known as toripalimab as evidenced by Tang (page 2 in col 2 in par 2). Disimitab vedotin of the claims comprises the antibody RC48 as evidenced by FDA (page 38 in col 1 in par 2).
It would have been obvious at the time the application was filed to combine the teachings of a method of treatment for cancer comprising the RC48-ADC where the ADC is linked to MMAE with a PD-1 antibody recited by the claims with the method of clinical trial of treating urothelial carcinoma with the same active therapeutics of RC48-MMAE and a PD-1 antibody. One of skill in the art would have been motivated by the teachings of Clinical Trial showing an additional application of the method of the instant claims. There would have been a reasonable expectation of success as Clinical Trial is teaching the same components of the reference application in a different cancer patients.
This is a provisional nonstatutory double patenting rejection.
Claims 2 and 16-17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-109 of copending Application No. 19564737 (Reference Application) in view of NCT04264936 (“Clinical Trial” PTO-892) (Published 02-13-2020) and Tang et al. Scientific Reports. 7:1-10. (2017) ( “Tang Y”PTO-892).
The recitations of the reference application from the previous double patenting rejection are incorporated here in full.
Regarding claim 2, the reference application recites the ADC of the instant claims by reciting a HER2 binding ADC of MMAE and an antibody where the heavy and light chains are SEQ ID NO: 9 and 11 which match instant SEQ ID NO: 1 and 2 thus teaching an ADC comprising the antibody of the sequences of instant claims 2, 8-9, 11, and 14 (claims 4-5). The reference application recites the drug is MMAE (claim 8) and the method comprising a PD-1 antibody (claims 1 and 16).
The teachings of Clinical Trial from the previous double patenting rejection are incorporated here in full.
The reference application in view of Clinical Trial does not teach the Drug to Antibody-ratio (DAR) for the HER2 binding ADC.
This deficiency is filled by Tang Y.
Tang Y teaches DAR of ADCs is important for therapeutic efficacy and pharmacokinetics (Abstract). Tang Y teaches most ADC drug candidates have their DAR maintained at about 2-4, which matches the 2-7 of instant claim 16, and 3.5 to 4.5 of instant claim 17 (page 1 in par 2). The ADCs of Tang Y include ones comprising MMAE (Figure 1).
It would have been obvious at the time the application was filed to combine the method of treating urothelial cancer of the reference application in view of Clinical Trial that comprises the use of a HER2 binding ADC and a PD-1 binding antibody with the DAR of about 2-4 of Tang Y as a starting dose. One of skill in the art would have been motivated to use commonly known to be effective DAR that is taught by art which Tang Y provides. There would have been a reasonable expectation of success as Tang Y provides art tested and known DAR for use in treatment of patients.
In regards to the specific dosage, in this case DAR, recited in the instant claims "[w]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955), and see M.P.E.P. § 2144.05 II.A. Moreover, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). This because, as is made clear from the prior art, the determination of the dosage regimen of a known drug is well within the purview of one of ordinary skill in the art at the time the invention was made, and it would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal DAR as DAR is an art-recognized result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. Therefore, it would be conventional and within the skill of the art to identify the optimal DAR administered to achieve target levels and therapeutically effective doses. Further, it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. It is clear that both the prior art and claimed method perform the same protocol to achieve the same results. It would be conventional and within the skill of the art to determine the optimal treatment regimens. Accordingly, one can see that the courts, over a period of over 50 years, have consistently held that treatment (ie DAR) optimization is obvious.
This is a provisional nonstatutory double patenting rejection.
Claims 2, 7, and 20-21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-109 of copending Application No. 19564737 (Reference Application) in view of NCT04264936 (“Clinical Trial” PTO-892) (Published 02-13-2020) and Vandeveer et. al. Cancer Immunol Res. 4(5):452-462. (2016) (PTO-892).
The recitations of the reference application from the previous double patenting rejection are incorporated here in full.
Regarding claim 2, the reference application recites the ADC of the instant claims by reciting a HER2 binding ADC of MMAE and an antibody where the heavy and light chains are SEQ ID NO: 9 and 11 which match instant SEQ ID NO: 1 and 2 thus teaching an ADC comprising the antibody of the sequences of instant claims 2, 8-9, 11, and 14 (claims 4-5). The reference application recites the drug is MMAE (claim 8) and the method comprising a PD-1 antibody (claims 1 and 16). The reference application recites toripalimab (claim 16).
The teachings of Clinical Trial from the previous double patenting rejection are incorporated here in full.
The reference application in view of Clinical Trial does not a PD-L1 binding
This deficiency is filled by Vandeveer.
Vandeveer teaches the use of the immune checkpoint inhibitor avelumab that binds PD-L1 for treatment in blader tumors to interrupt PD-1/PD-L1 signaling in cancer (abstract). Vandeveer teaches PD-L1 expression in the tumors (Figure 5).
Regarding claims 12-13, Vandeveer teaches avelumab is a human IgG1 antibody that interacts with PD-L1 and interrupts its signaling (page 454 in col 2 in par 3). Vandeveer teaches success treatment of cancer using avelumab alone (Figure 2).
It would have been obvious at the time the application to substitute the immune checkpoint inhibitor of the method of treating urothelial cancer of reference application in view of Clinical Trial that comprises the use of a HER2 binding ADC and a PD-1 binding antibody with the immune checkpoint inhibitor of avelumab taught by Vandeveer. The substitution would be prima facie obvious as toripalimab and avelumab are art equivalents that have the same biological activity of inhibiting PD-1/PD-L1 activity in tumors (MPEP 2144.09, 2144.00, and 2144.08). Further, Vandeveer teaches bladder cancer as PD-L1 positive, which avelumab binds. There would have been a reasonable expectation of success as Clinical Trial and Vandeveer both teach immune checkpoint inhibitors for use in treating cancer.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims allowable.
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/F.E./Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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