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 contains polynucleotide and/or polypeptide sequence information. Applicant is required to review the application 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 1-11 and 14-28 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.
The terms “the linking site” and “the interchain disulfide bond site” in claims 1 and 2 lack antecedent basis.
The rejected method claims recite a sample taken from a patient without reciting an active method step of taking the sample from the patient.
The structural criteria of “biosimilar” in claim 24 is not defined.
The term “the medicine” in claim 25 lacks antecedent basis.
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 1-4, 8-11, 14-28 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2015074528 as evidenced by: counterpart U.S. Publication No. 20160304621 based on an application by Fang et al. (Fang) and DATABASE CAPLUS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; Registry No. 2136633-23-1, Antibody-drug conjugate RC48, Disitamab vedotin, entered 29 October 2017 (Registry No. 2136633-23-1); in view of:
NCT04400695, A Study of RC48-ADC for the Treatment of Locally Advanced or Metastatic Breast Cancer With Low Expression of HER2, 2020 (Clinical Trial).
Regarding claims 1, 2, 3, Fang (see claims 1-13, examples 1, 6 and 9) discloses a conjugate of anti-HER2 antibody and small molecular medicine, Ab-(L-U)n, wherein the Ab presents anti-HER2 antibody, L presents a linker, U presents medicine, and n is an integer from 1 to 8. In an embodiment, the conjugate is RC48-vc-MMAE, wherein the anti-HER2 antibody is RC48, the linker is mc-vc-pAB and the small molecular medicine is MMAE. The linker is covalently linked to cysteine residue of RC48 by sulfhydryl.
See Figures:
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Cysteine conjugation, see above, suggests DAR ranges in claims 20 and 21.
RC48 comprises a VH and a VL, wherein the VH comprises HCDR 1-3 and the VL comprises LCDR 1-3 corresponding to the instant CDR’s:
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Regarding claim 14, the antibody is murine derived – see Example 1.
Registry No. 2136633-23-1 identifies RC48 as Antibody-drug conjugate RC48, Disitamab vedotin, corresponding to the VH, VL, heavy and light chains in these claims, and with the recited structure:
Immunoglobulin G1, anti-(human tyrosine kinase receptor ErbB2) (humanized monoclonal RC48-270A4023 γ1-chain), disulfide with humanized monoclonal RC48-270A4023 κ-chain, dimer, thioether with N-[[[4-[[N-[6-(3-mercapto-2,5-dioxo-1-pyrrolidinyl)-1-oxohexyl]-L-valyl-N5-(aminocarbonyl)-L-ornithyl]amino]phenyl]methoxy]carbonyl]-N-methyl-L-valyl- N-[(1S,2R)-4-[(2S)-2-[(1R,2R)-3-[[(1R,2S)-2-hydroxy-1-methyl-2-phenylethyl]amino]-1-methoxy-2-methyl-3-oxopropyl]-1-pyrrolidinyl]-2-methoxy-1-[(1S)-1-methylpropyl]-4-oxobutyl]-N-methyl-L-valinamide, see claims 15-19.
Breast cancer is taught, see example 9 (claims 8, 27).
Fang and Registry No. 2136633-23-1 may not explicitly teach Disitamab vedotin treatment of breast cancer with liver metathesis or without lung metathesis. However, Clinical Trials (see Study Identification, Study Description, Arms and Interventions and Eligibility) discloses a Phase III clinical trial of the efficacy and safety of recombinant humanized anti-HER2 monoclonal antibody-Monomethyl auristatin E (MMAE) conjugate (RC48-ADC, i.e., Disitamab vedotin) for the treatment of locally advanced or metastatic breast cancer. For inclusion criteria of liver function, ALT, AST and ALP were s5*ULN in the presence of liver metastasis.
Nonetheless, the references demonstrate Disitamab vedotin as effective treating breast cancer. Therefore, those of ordinary skill would expect that the ADC’s would be effective at treating breast cancer, whether in the presence of liver metathesis or absence of lung metathesis, with metathesis or unresectable (claims 8-11), with a reasonable expectation of success. Similarly, those of ordinary skill would expect that Disitamab vedotin would be effective after other therapies with concerning different targets or modes of action (see claims 22-24). In this way, it would have been obvious to administer Disitamab vedotin in these clinical situations.
Claims 25, 26 cover dosing regimens, routes of administration and effective amounts. However, optimizing cancer chemotherapy involves tailoring doses and schedules to maximize tumor cell destruction while minimizing toxic side effects and drug resistance. For example, the amount of Disitamab vedotin in the disclosed compositions of the prior art, and its dosing regiments are result-effective parameters that will affect the pharmacological and pharmacokinetic properties of the final composition. In this manner, the amount of a specific ingredient in a composition is clearly a result-effective parameter that a person of ordinary skill in the art would routinely optimize.
Specifically, it would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient to add in order to best achieve a desired results. For any compound, the therapeutically effective dose can be estimated initially either in cell culture assays or in animal models, usually rats, rabbits, dogs, or pigs. The animal model also can be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans.
Therapeutic efficacy and toxicity, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population), can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. The dose ratio of toxic to therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED5o. Pharmaceutical compositions which exhibit large therapeutic indices are preferred. The data obtained from cell culture assays and animal studies is used in formulating a range of dosage for human use. The dosage contained in such compositions is preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage varies within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration. The exact dosage will be determined by the practitioner, in light of factors related to the subject that requires treatment. Dosage and administration are adjusted to provide sufficient levels of the active ingredient or to maintain the desired effect. Factors which can be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions can be administered once or twice daily every 3 to 4 days, every week, or once every two weeks depending on the half-life and clearance rate of the particular formulation.
Normal dosage amounts can vary from micrograms to 100,000 micrograms, up to a maximum total dose, depending upon the route of administration. Guidance as to particular dosages and methods of delivery is provided in the literature and generally available to practitioners in the art.
In this way, optimization of these parameters is a routine practice, and consequently, would be prima facie obvious, absent factual evidence demonstrating an unexpected benefit of the claimed amount(s).
Claim 28 requires improved progression-free survival (PFS). However, any observed pharmacological effect of Disitamab vedotin, including PFS), is a necessary aspect of its administration, as disclosed by the applied references, and is therefore, prima facie obvious, see MPEP 2112.01 (“Products of identical chemical composition can not have mutually exclusive properties.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id.”).
Claims 5-7 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2015074528 as evidenced by: counterpart U.S. Publication No. 20160304621 based on an application by Fang et al. (Fang) and DATABASE CAPLUS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; Registry No. 2136633-23-1, Antibody-drug conjugate RC48, Disitamab vedotin, entered 29 October 2017 (Registry No. 2136633-23-1); in view of:
NCT04400695, A Study of RC48-ADC for the Treatment of Locally Advanced or Metastatic Breast Cancer With Low Expression of HER2, 2020 (Clinical Trial); in further view of: Park et al., Breast J, 2013, 20: 37-45, downloaded 16 April 2016 from ER and PR Immunohistochemistry and HER2 FISH versus Oncotype DX: Implications for Breast Cancer Treatment - Park - 2014 - The Breast Journal - Wiley Online Library (Park).
Claims 5-7 cover diagnosis using ER and PR immunohistochemistry. Park teaches that estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor (HER2) concordance between immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), and Oncotype DX, are commercially available as an RT-PCR-based assay which reports biomarker results.
In this way, using immunohistochemistry assays in this manner would have been well within the purview of those of ordinary skill, and thus, prima facie 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 1-11, 14-28 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 24-37 of copending Application No. 18/511,869 in view of Clinical Trials and Park (previously cited). Although the claims at issue are not identical, they are not patentably distinct from each other.
With regard to claims 1-4, 8-11, 14-28, the conflicting claims recite treating breast cancer with an ADC that anticipates the rejected claims. Alternatively, the difference between the methods covered by the conflicting claims and those covered by the rejected claims is that the conflicting claims do not recite the insta t methods 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 claimsrecite the elements of the instant methods 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).
The conflicting claims may not explicitly recite Disitamab vedotin treatment of breast cancer with liver metathesis or without lung metathesis. However, Clinical Trials (see Study Identification, Study Description, Arms and Interventions and Eligibility) discloses a Phase III clinical trial of the efficacy and safety of recombinant humanized anti-HER2 monoclonal antibody-Monomethyl auristatin E (MMAE) conjugate (RC48-ADC, i.e., Disitamab vedotin) for the treatment of locally advanced or metastatic breast cancer. For inclusion criteria of liver function, ALT, AST and ALP were s5*ULN in the presence of liver metastasis.
Nonetheless, the references demonstrate Disitamab vedotin as effective treating breast cancer. Therefore, those of ordinary skill would expect that the ADC’s would be effective at treating breast cancer, whether in the presence of liver metathesis or absence of lung metathesis, with metathesis or unresectable (claims 8-11), with a reasonable expectation of success. Similarly, those of ordinary skill would expect that Disitamab vedotin would be effective after other therapies with concerning different targets or modes of action (see claims 22-24). In this way, it would have been obvious to administer Disitamab vedotin in these clinical situations.
Claims 25, 26 cover dosing regimens, routes of administration and effective amounts. However, optimizing cancer chemotherapy involves tailoring doses and schedules to maximize tumor cell destruction while minimizing toxic side effects and drug resistance. For example, the amount of Disitamab vedotin in the disclosed compositions of the prior art, and its dosing regiments are result-effective parameters that will affect the pharmacological and pharmacokinetic properties of the final composition. In this manner, the amount of a specific ingredient in a composition is clearly a result-effective parameter that a person of ordinary skill in the art would routinely optimize.
Specifically, it would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient to add in order to best achieve a desired results. For any compound, the therapeutically effective dose can be estimated initially either in cell culture assays or in animal models, usually rats, rabbits, dogs, or pigs. The animal model also can be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans.
Therapeutic efficacy and toxicity, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population), can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. The dose ratio of toxic to therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED5o. Pharmaceutical compositions which exhibit large therapeutic indices are preferred. The data obtained from cell culture assays and animal studies is used in formulating a range of dosage for human use. The dosage contained in such compositions is preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage varies within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration. The exact dosage will be determined by the practitioner, in light of factors related to the subject that requires treatment. Dosage and administration are adjusted to provide sufficient levels of the active ingredient or to maintain the desired effect. Factors which can be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions can be administered once or twice daily every 3 to 4 days, every week, or once every two weeks depending on the half-life and clearance rate of the particular formulation.
Normal dosage amounts can vary from micrograms to 100,000 micrograms, up to a maximum total dose, depending upon the route of administration. Guidance as to particular dosages and methods of delivery is provided in the literature and generally available to practitioners in the art.
In this way, optimization of these parameters is a routine practice, and consequently, would be prima facie obvious, absent factual evidence demonstrating an unexpected benefit of the claimed amount(s).
Claim 28 requires improved progression-free survival (PFS). However, any observed pharmacological effect of Disitamab vedotin, including PFS), is a necessary aspect of its administration, as disclosed by the applied references, and is therefore, prima facie obvious, see MPEP 2112.01 (“Products of identical chemical composition can not have mutually exclusive properties.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id.”).
Claims 5-7 cover diagnosis using ER and PR immunohistochemistry. Park teaches that estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor (HER2) concordance between immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), and Oncotype DX, are commercially available as an RT-PCR-based assay which reports biomarker results. In this way, using immunohistochemistry assays in this manner would have been well within the purview of those of ordinary skill, and thus, prima facie obvious.
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
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