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 .
Information Disclosure Statement
The Information Disclosure Statement (IDS) filed on 11/27/2023 has been considered.
Claim Status
The preliminary amendment filed May 06, 2024 has been entered. Claims 2 and 17-20 are canceled. Thus, claims 1, 3-16 and 21-25 as amended are examined on the merits herein.
Claim Objections
Claims 8 and 10 are objected to because of the following informalities:
Claim 8, line 2, recites “pancreatic cancer” which is clearly missing the article “a” immediately before “pancreatic”. Thus, to promote clarity the Examiner suggests inserting the article “a” immediately before the phrase “pancreatic cancer” as discussed above.
Claim 10, lines 1-2, recite “a therapeutically effective amount” which the Examiner respectfully notes is already recited in claim 1, line 2. Additionally the Examiner notes claim 10 depends from claim 1. Thus, to promote clarity the Examiner suggests replacing the article “a” with the word “the” as discussed above.
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 4 and 13 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.
Regarding claims 4 and 13, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 4, line 2, recites “such as” when referring to the immune checkpoint inhibitor.
Claim 13, line 2, recites “such as” when referring to the method of systemic administration of 6-thio-dG.
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.
Claims 1, 6-16 and 21-25 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Shay et al. (Published 09 October 2014, US-20140303239-A1, IDS filed 11/27/2023) as evidenced by Vinagre (Published 26 July 2013, Nature Communications, Vol. 4, Article Number 2185, pp. 1-6, IDS filed 11/27/2023) and Gaspar et al. (Published 03 May 2018, Genes, Vol. 9, Issue 5, pp. 1-58, PTO-892).
Regarding claims 1, 6-16 and 21-25, Shay teaches pharmaceutical compositions and methods of using 6-mercaptopurine ribosides and analogs thereof for the treatment of cancer, wherein the described compounds can be converted into telomere substrates in vivo and can be recognized by telomerase for incorporation into telomeres of telomerase active cells, leading to induction of cell death of the telomerase active cells, see abstract.
Shay teaches administration of the various pharmaceutical compositions represent an approach to treatment of telomerase positive human cancers (required in claim 1, line 3) based on a bifunctional mechanism of action characterized as i) acute cytotoxicity derived from anti-metabolic properties and incorporation into genomic DNA (e.g. impaired cancer cell viability, required in claim 1, line 2) and ii) telomeric DNA modification and shortening (e.g. required in claim 21, lines 3-4), see paragraph [0033].
Shay teaches the pharmaceutical compositions and therapeutic approaches involving the compounds have an anti-cancer effect, see paragraphs [0003] and [0044]; wherein “anti-cancer effect” is defined to include inhibiting further growth of the tumor or cancer cells, reducing the likelihood or eliminating metastasis, resulting in shrinkage of the tumor and the cancer is in remission (e.g. the results, required in claim 22), see paragraph [0044].
Shay teaches the cancer may specifically be of the following histological type including malignant melanoma (e.g. the melanoma, required in claim 8), see paragraph [0047]. The Examiner respectfully notes that the recitation of malignant melanoma fulfills the recitation of “cells of said cancer exhibit (a) TERT promoter mutations and/or (b) enriched telomere transcriptional signatures(s)” as required in claim 1, lines 3-4, as the Examiner reasonably interprets these limitations as physical limitations of melanoma as evidenced by Applicants Specification which discloses “it is known that TERT mutations are very common in melanoma, as are enriched telomere transcriptional signatures (see pg. 14, lines 3-4).
Shay teaches the cancer may be metastatic cancer, and in certain embodiments the cancer may originate in the skin (e.g. the metastatic cancer, required in claim 25), see paragraph [0046].
Shay teaches treatment comprises administering an effective amount of 6-mercaptopurine ribonucleoside analogue, see paragraph [0017]; wherein Shay exemplifies administering to a subject, wherein the subject has been diagnosed with cancer, a pharmaceutical composition comprising a 6-mercaptopurine ribonucleoside analogue known as 6-thio-2’-deoxyguanosine, see pg. 12, left column, claim #2.
Shay defines “subject” to include either a human (e.g. the subject, required in claim 15) or non-human, exemplifying primates (e.g. the subject, required in claim 16), see paragraph [0045].
Shay teaches the effective amount of the pharmaceutical composition is administered to the subject per day (e.g. daily, required in claims 11-12) and the effective amount comprises an amount between 0.5 mg of the analogue per 1 kg of subject to 3 mg of the analogue per 1 kg of subject (e.g. the effective amount, required in claim 10), see pg. 13, claim #7.
Shay teaches the pharmaceutical composition is administered orally (e.g. administered systemically, required in claim 13), see pg. 13, claim #15.
Shay teaches the pharmaceutical composition is administered by intratumoral injection (e.g. administered intratumorally, required in claim 14), see pg. 13, claim #16.
Moreover, Vinagre discloses frequency of TERT promoter mutations in human cancers, see pg. 1, title; where the presence of recurrent somatic mutations in the TERT promoter in cancer of the skin, i.e. melanoma, is 29%, see pg. 1, abstract; and discloses ten out of sixteen (63%) skin melanomas with TERT mutation also harboured the BRAFV600E mutation (e.g. the BRAFV600 mutant, required in claims 6-7), see pg. 2, left column, TERT mutations in melanoma, paragraph 1.
Furthermore, Gaspar discloses a telomerase-independent mechanism of telomere lengthening known as alternative lengthening of telomeres, see pg. 26, 2.2.6 alternative lengthening of telomeres (ALT), paragraph 1; wherein the prevalence of the ALT phenotype in tumor subtypes is shown in Table 4, see pg. 27, paragraph 3; where Table 4 discloses the prevalence of ALT in malignant melanoma is 6.6% (e.g. the telomere maintenance signature, required in claim 9), see, pg. 15, Table 4, tumors of the skin.
With respect to limitations (a) “further comprising assessing a cancer cell from said subject for one or more of (i) TERT promoter mutation, (ii) enriched telomere transcriptional signature(s) and (iii) one or more B-Raf mutations”, required in claim 23; and “wherein the enriched telomere transcription signature is a telomere maintenance signature”, required in claim 24; the Examiner reasonably interprets these limitations as physical limitations of “a subject with cancer” as recited in claim 1, line 1. Since Shay teaches pharmaceutical compositions representing an approach to treatment of telomerase positive human cancers, wherein said composition comprises 6-thio-2’-deoxyguanosine; by administering to a subject said composition, wherein the subject has been diagnosed with cancer; wherein the cancer is exemplified as malignant melanoma as taught by Shay above; and as further evidenced by Vinagre disclosing TERT promoter mutations and B-Raf mutations are present in malignant melanoma, as well as evidenced by Gaspar disclosing alternative lengthening of telomerases (ALT) as a telomerase-independent mechanism present in malignant melanoma; the teachings of Shay as evidenced by Vinagre and Gaspar above will meet limitations (a)-(b) as discussed above.
Thus, the teachings of Shay as evidenced by Vinagre and Gaspar above anticipated claims 1, 6-16 and 21-25 as discussed above.
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 3-5 are rejected under 35 U.S.C. 103 as being unpatentable over Shay et al. (Published 09 October 2014, US-20140303239-A1, IDS filed 11/27/2023) as evidenced by Vinagre (Published 26 July 2013, Nature Communications, Vol. 4, Article Number 2185, pp. 1-6, IDS filed 11/27/2023) and Gaspar et al. (Published 03 May 2018, Genes, Vol. 9, Issue 5, pp. 1-58, PTO-892) as applied to claims 1, 6-16 and 21-25 above, and further in view of Hugo et al. (Published 10 September 2015, Cell, Vol. 162, Issue 6, pp. 1271-1285, IDS filed 11/27/2023).
Shay as evidenced by Vinagre and Gaspar address claims 1, 6-16 and 21-25 as written above. Although, Shay does not teach said subject has had disease progression during or after immunotherapy and/or MAPKi therapy, required in claims 3-5.
However, in the same field of endeavor of therapies for melanoma, Hugo analyzed whole-exome sequences (WESs) of serial tumor biopsies (baseline and acquired resistant tumors) and normal tissues from patients with advanced melanoma treated with MAPK inhibitor (MAPKi) regiments, including single-drug (i.e. BRAFi) and double-drug (i.e. BRAFi+MEKi) therapies; and when multiple disease progressive or acquired MAPKi-resistant tumors were obtained from patients they were compared to the same patient-matched baseline tumors. Hugo visualized the recurrence of these mutations specific to or highly enriched in single-drug and double-drug disease-progressive melanomas (n=67) relative to matched baseline tumors (Figure 1A); wherein functionally validated mutations included gain of function (GOF) events including V600E/KBRAF, and the most recurrent resistance mutations were detected almost mutually exclusively and included V600E/KBRAF. See pg. 1273, left column, genetic mechanisms of acquired MAPKi resistance in melanoma, paragraph 1.
Hugo further discloses matrix of disease progressive melanomas (n=67; indicated by patient and then tumor numbers) on BRAFi or BRAFi-MEKi therapies and of genes whose mutations cause acquired MAPKi resistance, where Hugo depicts in the bottom of Figure 1(A) shows BRAF variant allelic frequencies or VAFs (resulting in V600E/K) adjusted by estimated tumor impurities, see pg. 1272, Figure 1(A).
Hugo also observed CTLA4 down-expression in several acquired MAPKi-resistant melanoma cell lines compared to their parental counterparts, see pg. 1274, left column, paragraph 2. Additionally, Hugo teaches in the current therapeutic landscape, salvage therapies for patients with disease progression on MAPKi often involve immunotherapies, e.g. inhibitors of CTLA-4 and PD-1 checkpoints, see pg. 1271, right column, paragraph 3.
It would have been prima facie obvious to one of ordinary skill in the art at the invention’s effective filing date to have included the subject having disease progression during or after immunotherapy and/or MAPKi therapy as within the scope of the artisan as combining prior art elements according to known compositions and methods to yield predictable results. One of ordinary skill in the art would have been motivated to include these limitations as Shay treats a subject having cancer, exemplified as malignant melanoma, wherein as taught by Hugo above results in melanoma progression after either BRAFi or BRAFi-MEKi therapies and where Hugo also observed CTLA4 down-expression in several acquired MAPKi-resistant melanomas; which Hugo further teaches inhibitors of the CTLA-4 and PD-1 checkpoints are known therapies for patients with disease progression on MAPKi as discussed above. Therefore, one of ordinary skill in the art would have had a reasonably expectation of success to have included the disease progression limitations discussed above; as Hugo shows BRAF variant allelic frequencies (VAFs) resulting in V600E/K variants in disease progressive melanomas on BRAFi or BRAFi-MEKi therapies and of genes whose mutations cause acquired MAPKi resistance as discussed above; and as further evidenced by the disclosure of Vinagre stating ten out of sixteen (63%) skin melanomas with TERT mutation also harboured the BRAFV600E mutation as discussed above.
Thus, it would have been prima facie obvious to one of ordinary skill in the art before the invention was filed to have incorporated the disease progression during or after immunotherapy and/or MAPKi therapy as required in instant claims 3-5 into the method of Shay as discussed above as combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to treat the subject having cancer, specifically malignant melanoma as taught by Shay above. One of ordinary skill in the art would have had a reasonable expectation of success of including the disease progression during or after immunotherapy and/or MAPKi therapy as discussed above, as both Shay and Hugo are drawn to treating subjects with melanoma; Hugo discloses BRAF variant allelic frequencies result in V600E/K variants in disease progressive melanomas on BRAFi or BRAFi-MEKi therapies; and Hugo observed CTLA4 was down-expressed in several acquired MAPKi-resistant melanoma cell lines compared to their parental counterparts; and wherein immunotherapies, e.g. inhibitors of CTLA-4 and PD-1 checkpoints, are known therapies for patients with disease progression on MAPKi as discussed above.
Thus, the claimed invention as a whole would have been prima facie obvious over the combined teachings of the prior art.
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, 6-8, 10-16, 21-23 and 25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 and 4-7 of U.S. Patent No. 10,463,685 (Applicant: The Board of Regents of the University of Texas System, PTO-892) in view of Ma et al. (Published 23 October 2014, Lung Cancer, Vol. 86, Issue 3, pp. 369-373, PTO-892). Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are drawn to administering 6-thio-2'-deoxyguanosine as a treatment of cancer in a subject; wherein said cancer cells are telomerase-positive and exhibit one or more TERT promoter mutations.
Reference claim 1 recites treating a telomerase-expressing lung cancer cell characterized by an over-activation of telomerase in a subject in need thereof with lung cancer, comprising administered a pharmaceutical composition comprising a compound analogue according to formula III; wherein the pharmaceutical composition is administered in an amount effective to reduce stability of telomere length and to induce cell death (e.g. apoptosis, required in instant claim 21) in the telomerase-expressing lung cancer cell.
The Examiner respectfully notes that when R1 is H as recited in reference claim 1 it corresponds to the compound 6-thio-2’-deoxyguanosine as evidenced by the Specification in Figure 1A. The Examiner also respectfully notes that the Specification defines “subject” to include humans and primates.
Reference claim 2 recites the pharmaceutical composition is administered in an amount between 0.5-3 mg per 1 kg of the subject per day.
Reference claim 4 recites the administering of the pharmaceutical composition is orally.
Reference claim 5 recites the administering of the pharmaceutical composition is by intratumoral injection.
Reference claim 6 recites wherein the subject is a human being.
Reference claim 7 recites wherein the amount effective to reduce stability of telomere length and induce cell death in the telomere-expressing lung cancer cell effects a reduction in tumor size (e.g. reduction in primary tumor size, required in instant claim 22) of a lung tumor comprising the telomerase-expression lung cancer cell.
Although, ‘685 does not recite (a) “wherein cells of said cancer exhibit one or more TERT promoter mutations, as required in instant claim 1, lines 3-4; (b) the BRAF mutant, as required in instant claims 6-7; and (c) wherein said cancer is metastatic, as required in instant claim 25.
However, in the same field of endeavor of lung cancer, with respect to limitations (a)-(c), Ma teaches recurrent TERT promoter mutations in non-small cell lung cancers, see pg. 269, title; where activation mutations in TERT promoter leads to increased expression of telomerase, which maintains telomere length and genomic stability, thereby allowing cancer cells to continuously divide and avoiding senescence or apoptosis, see pg. 369, right column, paragraph 1. Ma teaches BRAF mutations could activate the expression of TERT by MAPK pathway (e.g. the BRAF mutant, required in instant claims 6-7), see pg. 372, right column, discussion, paragraph 2.
Ma teaches in Table 1 clinical characteristics of 12 patients with lung cancers with TERT promoter mutations wherein ID# 902 is a male subject, 64 years of age with a TERT C216T mutation and lymph node status N2 (e.g. the metastatic cancer, required in instant claim 25), see pg. 372, Table 2, ID 902.
With respect to the limitation “further comprising assessing a cancer cell subject for a TERT promoter mutation”, required in instant claim 23; the Examiner reasonably interprets this limitation as physical limitation of “a subject with cancer” as recited in instant claim 1, line 1. Since ‘685 recites pharmaceutical compositions comprises 6-thio-2’-deoxyguanosine; by administering to a subject said composition, wherein the subject has lung cancer; and Ma teaches lung cancers with TERT promoter mutations as discussed above; the recitations of ‘685 and teachings of Ma above will meet the physical limitation as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art before the invention was filed to have included limitations (a)-(c) into the treatment recited in ‘685 as within the scope of the artisan as combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to treat the subject with lung cancer as recited by ‘685 above. One of ordinary skill in the art would have had a reasonable expectation of success to have incorporated limitations (a)-(c) into the treatment recited by ‘685, as ‘685 recites treating a telomerase-expressing lung cancer cell characterized by an over-activation of telomerase in a subject wherein the pharmaceutical composition is administered in an amount effective to reduce stability of telomere length; and Ma teaches TERT mutations in lung cancer; and wherein activation mutations in TERT promoter leads to increased expression of telomerase which maintains telomere length and genomic stability as discussed above.
Thus, the claimed invention as a whole would have been prima facie obvious over the combined recitations of ‘685 and the teachings of the prior art.
Conclusion
No claims are allowed in this action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JARET J CREWS whose telephone number is (571)270-0962. The examiner can normally be reached Monday-Friday: 9:00am-5:30pm EST.
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/JARET J CREWS/Examiner, Art Unit 1691
/RENEE CLAYTOR/Supervisory Patent Examiner, Art Unit 1691