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 .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Current Status of 18/272,419
This Office Action is responsive to the amended claims received 19 October 2023.
Claims 1-19 are currently pending.
Priority
Applicant’s claim for the benefit of the prior-filed patent applications PCT/NL2022/050016 (filed 17 January 2022) and EP 21151844.4 (filed 15 January 2021) under 35 U.S.C. 119(e), 120, 121, 365(c), or 386(c) is acknowledged.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement (IDS) received on 14 July 2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, this information disclosure statement is being considered by the examiner.
Drawings
New corrected drawings in compliance with 37 CFR 1.121(d) are required in this application for the following reasons: Figures 1-6 and 9-10 are labeled with some variation of “Figure 1” and “Figure 1 (continued)”. Title 37 CFR § 1.84(u)(1) states that partial views “must be identified by the same number followed by a capital letter”. Applicant may choose to relabel each panel of “Figure 1” and “Figure 1 (continued)” as “Figure 1A”, “Figure 1B”, and so on, along with relabeling the other figures listed above in an analogous manner. Figure 2, panel B contains two different types of data markers that are grey squares, which cannot be differentiated. Figure 2, panels C and E contain text that is too small and/or low-resolution to be legible. Figure 3, panels D-F contain text that is too small and/or low-resolution to be legible. Figure 4, panels A-B contain multiple grey, circular data markers that are indistinguishable. Figure 5, panel A contains text that is too small and/or low-resolution to be legible. Figure 6, panel A contains text that is too small and/or low-resolution to be legible.
Applicant is advised to employ the services of a competent patent draftsperson outside the Office, as the U.S. Patent and Trademark Office no longer prepares new drawings. The corrected drawings are required in reply to the Office action to avoid abandonment of the application. The requirement for corrected drawings will not be held in abeyance.
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:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). The instant specification includes sequence identifies of the form “SEQ 5.”, which differs from the required sequence identifier of “SEQ ID NO: 5”, for example.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Objections
Claim 10 is objected to because of the following informalities: Claim 10 recites the phrase “involving senescent cells, said method comprises”. This is grammatically incorrect. Applicant may choose to replace the quoted phrase above with “involving senescent cells, wherein said method comprises”. Appropriate correction is required.
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 1-8 and 15-16 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.
Claim 1 recites “administering… a selective Death Receptor 5 (DR5) to the patient”. This phrase is unclear, because a reader would be confused whether the artisan is to administer a receptor to the patient, which seems unlikely, or a DR5 agonist to the patient, which seems likely but is not described by the text of the claim. Also, the claim refers to “the selective DR5 agonist” further on, which lacks antecedent basis. This renders claims 1-8 indefinite. To correct both of these unclear phrases, Applicant may insert the term “agonist” into the first quoted phrase above.
Claims 3 recites the phrase “the inducer”. This term lacks antecedent basis, as it is not clear what term in the parent claim is being referred to. This renders claim 3 indefinite. Applicant may choose to replace the quoted phrase above with “the inducer of senescence”, as is currently written in claim 2.
Each of claims 15 and 16 recite “a BRD2 inhibitor”. This term is unclear to the reader, because “a BRD2 inhibitor” is already established by the parent claim, claim 14. The reader will be confused whether the BRD2 inhibitor in claims 15 and 16 is somehow different from the previously established BRD2 inhibitor. This renders claims 15-16 indefinite. Applicant may choose to use the word “the” to refer the BRD2 inhibitors in claims 15-16.
Claim 16 recites “a selective Death Receptor 5 (DR5) agonist”. This term is unclear to the reader, because the parent claim already establishes a selective Death Receptor 5 (DR5) agonist. This renders claim 16 indefinite. Applicant may choose to use the word “the” to refer the selective Death Receptor 5 (DR5) agonist in claim 16.
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 1-4, 6, 8, 14, and 17-18 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by:
BRUNKER (Brunker, P.; Wartha, K.; Friess, T.; “RG7386, a Novel Tetravalent FAP-DR5 Antibody, Effectively Triggers FAP-Dependent, Avidity-Driven DR5 Hyperclustering and Tumor Cell Apoptosis” Mol Cancer Ther; 15(5) May 2016)
as evidenced by:
KLEIN (Klein, C.; Schaefer, W.; Regula, J.T. “Engineering therapeutic bispecific antibodies using CrossMab technology” Methods 154 (2019) 21–31).
BRUNKER teaches RG7386 to be a bispecific antibody that acts as a Death Receptor 5 (DR5) agonist (abstract and 2nd paragraph of Pg. 947). BRUNKER teaches this antibody to be useful as an anti-cancer therapy (abstract). BRUNKER states that RG7386 contains the VL and VH chains from drozitumab (Pg. 947, 4th paragraph), being a human IgG antibody (Pg. 947 1st paragraph). BRUNKER teaches the administration of a drug cocktail including RG7386 and doxorubicin, and shows that this is more effective than either individual agent at decreasing the size of osteosarcoma tumors in a mouse model (Pg. 953 last paragraph – Pg. 954 1st paragraph and Fig. 6C). BRUNKER teaches that RG7386 was administered to mice once per week and doxorubicin was administered to mice at 5 mg/kg intravenously once per week (Pg. 949, 3rd paragraph).
BRUNKER does not directly state the half-life of the bispecific RG7386 IgG human antibody taught therein, although the weekly dosing of the antibody is described. KLEIN provides evidence that vanucizumab is a bispecific IgG humanized antibody with a half-life of 6-9 days (Pg. 24, 2nd paragraph). One of ordinary skill in the art, reading the teachings of BRUNKER, and knowing about the half-life of similar antibodies, would assume the half-life of the antibody of BRUNKER to be similar to that of vanucizumab, about 6-9 days.
Regarding claim 8: BRUNKER teaches the use of the RG7386 antibody therein to cause apoptosis in a breast cancer model (Pg. 952, 2nd paragraph and Fig. 3, panel B).
Regarding claims 4 and 14: BRUNKER teaches that RG7386 was administered to mice once per week and doxorubicin was administered to mice at 5 mg/kg intravenously once per week (Pg. 949, 3rd paragraph). Because these compounds were not taught to be administered simultaneously, one of ordinary skill in the art would have read this dosing information to indicate that one of these compounds was administered, then the other, and so on. This reads on instant claims 4 and 14.
Regarding claim 18: The instant specification describes that senescent cells can arise from tumor cells, in response to the administration of chemotherapeutic agents. Logically, this would indicate that senescent cells, as instantly defined, were present within the mice bearing osteosarcoma tumors of BRUNKER, which were taught to have been treated with doxorubicin and RG7386.
Claims 1-2, 6-13, and 18-19 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by:
WANG (WO 2019/165340 A1; International Publication Date 29 August 2019)
as evidenced by:
DAVIS (Davis, S.K.; Selva, K.J.; Kent, S.J.; Chung, A.W. “Serum IgA Fc effector functions in infectious disease and cancer” Immunology & Cell Biology 2020; 98: 276–286).
WANG teaches a method of treating cancer in a subject through the administration of a chemotherapeutic agent and a dimeric IgA antibody that is capable of agonistically binding to DR5 (claim 1). Paragraph [0065] of WANG teaches that the antibodies therein may be human or humanized. Paragraph [0095] of WANG teaches that the therapies therein may be used to treat breast carcinomas. WANG teaches pharmaceutical compositions of the antibodies therein (paragraph [0162]). WANG specifically teaches the combination of an anti-DR5 antibody and a chemotherapeutic into a single pharmaceutical composition (paragraph [0151]).
DAVIS provides evidence that IgA antibodies are rapidly catabolized and this causes IgA antibodies to have a short half-life of 4-6 days (Last paragraph of Pg. 276, continues onto next page).
Regarding claims 10 and 18-19: The instant specification describes that senescent cells can arise from tumor cells, in response to the administration of chemotherapeutic agents. Logically, this would indicate that senescent cells, as instantly defined, would be present within the subject of the method of claim 1 of WANG, because a chemotherapeutic agent is used within that method.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-4, 6, 8, and 14-18 are rejected under 35 U.S.C. 103 as being unpatentable over:
BRUNKER (Brunker, P.; Wartha, K.; Friess, T.; “RG7386, a Novel Tetravalent FAP-DR5 Antibody, Effectively Triggers FAP-Dependent, Avidity-Driven DR5 Hyperclustering and Tumor Cell Apoptosis” Mol Cancer Ther; 15(5) May 2016)
as evidenced by:
KLEIN (Klein, C.; Schaefer, W.; Regula, J.T. “Engineering therapeutic bispecific antibodies using CrossMab technology” Methods 154 (2019) 21–31).
Teachings of BRUNKER are described in the 35 USC 102 rejections above. BRUNKER does not explicitly teach the timing of the administration of therapeutics required by instant claims 15 and 16.
Regarding claims 15-16: It would have been obvious to one of ordinary skill in the art, before the instant effective filing date, to experiment with the dosing regimen taught by BRUNKER, for the purpose of increasing the anti-cancer efficacy of the therapy and decreasing unwanted effects of the therapeutic agents. It would have been obvious to temporally separate the administration of the DR5 agonist of BRUNKER from the administration of the inducer of senescence by at least 24 hours to lower the intensity of unwanted effects of these drugs. While BRUNKER teaches weekly administration of the compounds therein, it would have been obvious to test tapering off of these compounds toward the end of a treatment regimen, and it would have been obvious for this tapering off to result in administration once every other week. This type of dosing regimen experimentation would have been an obvious form of routine experimentation. See MPEP 2144.05(II)(A).
Claims 1-6, 8, and 14-18 are rejected under 35 U.S.C. 103 as being unpatentable over:
BRUNKER (Brunker, P.; Wartha, K.; Friess, T.; “RG7386, a Novel Tetravalent FAP-DR5 Antibody, Effectively Triggers FAP-Dependent, Avidity-Driven DR5 Hyperclustering and Tumor Cell Apoptosis” Mol Cancer Ther; 15(5) May 2016)
as evidenced by:
KLEIN (Klein, C.; Schaefer, W.; Regula, J.T. “Engineering therapeutic bispecific antibodies using CrossMab technology” Methods 154 (2019) 21–31)
in view of:
TAN (Tan, X.; Tong, J.; Wang, Y.J. “BET Inhibitors Potentiate Chemotherapy and Killing of SPOP-Mutant Colon Cancer Cells via Induction of DR5” Cancer Res; 79(6) March 15, 2019).
Teachings of BRUNKER are described in the 35 USC 102 and 35 USC 103 rejections above. BRUNKER does not explicitly teach the incorporation of a BRD2 inhibitor, as required by instant claim 5.
Regarding claim 5 (BRD2): TAN teaches that a bromodomain and extraterminal domain (BET) inhibitor, alone or in combination with a chemotherapy, was effective against colorectal cancer during enhanced DR5 induction (abstract). Specifically, a colorectal cancer cell line, HCT116, was taught to be treated with I-BET151 by TAN (top right of Pg. 1193) (I-BET151 is defined on Pg. 22 of the instant specification as a BRD2 inhibitor). Figure 1, panel C of TAN shows that treatment with I-BET151 was successful in inducing DR5 expression. TAN teaches that the combination of a BET inhibitor with oxaliplatin, a chemotherapeutic, “markedly improved therapeutic efficacy in colorectal cancer cells” (discussion).
It would have been obvious to one of ordinary skill in the art, before the instant effective filing date, to test each of the BET inhibitors taught by TAN (including I-BET151 and three other compounds) in combination with the cocktail of RG7386 and doxorubicin taught by BRUNKER, for the purpose of increasing the anti-cancer efficacy of the RG7386 drug cocktail. The artisan would have expected success in this combination, because TAN taught that the BET inhibitors therein were performing the same anti-cancer function as the RG7386 molecule of BRUNKER, which was activating DR5.
Conclusion
No claims are currently allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOHN D MCANANY whose telephone number is (571)270-0850. The examiner can normally be reached 8:30 AM - 5:30 PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, ANDREW D KOSAR can be reached at (571)272-0913. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JDMc/Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625