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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on April 16, 2026 has been entered.
Claim Interpretation
Claim 21 recites a polypeptide comprising the sequence SEQ ID NO: 1 or a functionally equivalent variant thereof. Functionally equivalent variant thereof is defined on page 12 of the instant Specification as “any polypeptide which results from the insertion or addition of one or more amino acids and/or from the deletion of one or more amino acids and/or from the conservative substitution of one or more amino acids with respect to the polypeptide of SEQ ID NO: 1 and/or which results from the chemical modification of the polypeptide of SEQ ID NO: 1 and which substantially preserves the tumor suppressor activity of the SEQ ID NO: 1.” There is no limit to the number of amino acids which can inserted and/or deleted and/or conservatively substituted and there is no requirement that a minimum sequence identity to the length of SEQ ID NO: 1 be maintained. The only requirement of a functionally equivalent variant is that it demonstrate substantially preserved tumor suppressor activity of SEQ ID NO: 1. The Specification states that “preservation of the tumor suppressor activity requires that the variant can dimerize with Myc and/or its obligate partner p21/p22Max and inhibit Myc activity, that it is capable of translocating across the cell membrane and that it is capable of translocating across the nuclear envelope.”
Wang et al. (Oncogene. 38: 140-150; Published: August 3, 2018) teaches that a cell penetrating peptide is critical to the tumor suppressor function of Omomyc. Figure 1b and 1c demonstrate that the presence of a functional cell penetrating peptide (FPPa) is necessary to achieve statistically significant tumor suppressor activity across murine and human cell lines compared to Omomyc without the FPPa.
Additionally, Wang et al. teaches the sequence of OmoMyc which is 1005 identical to SEQ ID NO: 1; see Figure 1a. OmoMyc is a bHLH-Zip protein which mimics the bHLH-Zip domain of Myc by incorporating the following point mutations; E63T, E70I, R77Q, and R78N which inhibit Myc – Max binding; see page 142 right column. Soucek et al. (Oncogene. 17: 2463-2472; Published: October 12, 1998) teaches that residues E57, E64, R70, and R71, mutated as E57T, E64I, R70Q, and R71N and which correspond with E63, E70, R77, and R78 in the Wang et al. reference, are critical to the dimerization of Myc; see page 2464 right column. Thus, Wang et al. and Soucek et al. combined provide a structure – function correlation for translocation across the nuclear envelope, dimerization with Myc or Max, and inhibition of Myc activity.
Further, the instant Specification provides further guidance on substitutions to the critical residues taught in Wang et al. and Soucek et al.; see page 14. Additionally, the instant Specification of discloses the subsequence within SEQ ID NO: 1 which is responsible for nuclear localization, not cell penetration, and the sequences of seven functionally equivalent variants (SEQ ID NO: 4-10); see pages 11 and 16.
Thus, while the limitation of functionally equivalent variant is broad, one of ordinary skill in the art would conclude that Applicant was in possession of the genus of functionally equivalent variants by both the disclosure of a structure – function correlation and a representative numbers of species.
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 21-25, 30-37, 39, and 40-42 are rejected under 35 U.S.C. 103 as being unpatentable over Soucek et al. (WO 2014/180889 A1; Published: November 13, 2014) and Felsher et al. (WO 2017/152132 A1; Published: September 8, 2017) in view of the Pembrolizumab Approval Announcement (FDA; Published: May 10, 2017) and Ock et al. (Nature Communications. 8: 1050: Published: October 19, 2017).
Regarding claims 21 and 32, Soucek et al. teaches a combination of a polypeptide 100% identical to instant SEQ ID NO: 1 with an anti-tumoral agent; see claim 15, the translated sequence on pages 8-9, and pages 25-28.
Regarding claim 22, Soucek et al. teaches the variant called Omomyc*LZArg, which comprises SEQ ID NO: 48, on page 15. Residues 1-92 of SEQ ID NO: 48 are 100% identical to SEQ ID NO: 4.
Regarding claims 23-25, Soucek et al. claims 6-9 teach that the polypeptide or functionally equivalent variant is a fusion protein comprising a cell penetrating peptide sequence selected from SEQ ID NOs: 28 and 29, which are 100% identical to instant SEQ ID NO: 37 and 38, and further comprises a nuclear localization signal.
Regarding claims 33 and 34, Soucek et al. teaches using the polypeptide of pharmaceutical composition comprising an anti-tumoral agent for the treatment of cancer and that lung cancer is the preferred embodiment; see claims 20 and page 16 lines 30-32.
Regarding claims 35 and 36, Soucek et al. teaches intranasal administration or instillation into the nose; see page 32 lines 29-32 and page 33 lines 5-8. Further, regarding claim 37, Soucek et al. teaches that the components of the composition may be formulated differently so that the components can be differently administered and exemplifies the second component being administered intravenously, or a form of systemic administration; see page 31 lines 9-13.
While Soucek et al. teaches combination regimens with the Myc inhibitor of SEQ ID NO: 1, Soucek et al. does not teach a combination or composition wherein the second component is an immune checkpoint inhibitor nor does Soucek et al. teach treating cancer with a combination or composition comprising an immune checkpoint inhibitor.
Felsher et al. teaches the method of identifying whether a subject having cancer will be responsive to an immune checkpoint inhibitor comprising determining from a sample that the cancer overexpresses a Myc oncogene, identifying the subject with Myc oncogene overexpression as responsive to immune checkpoint inhibition, and administering an immune checkpoint inhibitor, including a PD-1 inhibitor; see claims 1 and 6.
Regarding claims 21, 32, and 33, Felsher et al. suggests that a Myc inhibitor and immune checkpoint inhibitor may be used in combination to treat cancer; see Summary on page 2. Regarding the Myc inhibitor of claim 21, Felsher et al. teaches a Myc inhibitor with the sequence of SEQ ID NO: 19, which is 100% identical to instant SEQ ID NO: 1, or a variant thereof. Regarding the immune-oncology agent of claims 21, 30, and 31, Felsher et al. teaches several PD-1/PD-L1 pathway inhibitors, including pembrolizumab, an anti-PD-1 antagonist antibody. Regarding the anti-CTLA-4 antibody of claims 1, 41, and 42, Felsher et al. teaches that the immune checkpoint inhibitor may comprise an anti-CTLA-4 antibody, including ipilimumab; see pages 14 and 36 miswritten as “CLTA4”.
Regarding claims 39 and 40, the recruitment of T cells to the tumor site, the expansion of T regulatory cells, and induction of IFN-gamma are all inherent properties of claim 33. The claim requires only that a therapeutically effective amount of the combination or composition of claim 21 be administered to a subject in need thereof and no additional steps are recited. Thus, these are outcomes which would inherently flow from the administration of the combination of the polypeptide and the immune-oncology agent.
Given that Felsher et al. teaches the positive relationship between Myc expression and PD-L1 expression in human cancers, including non-small cell lung cancer, and suggests treating a subject, who has been identified as responsive to immune checkpoint inhibitors by Myc overexpression, with a Myc inhibitor and an immune checkpoint inhibitor, it would have been obvious to treat cancer using a combination of the Myc inhibitor comprising SEQ ID NO: 1 or a variant thereof as taught by Soucek et al. with the anti-PD-1 antibody, pembrolizumab, as taught by Felsher et al. Further, one would have been motivated to make the combination because Felsher et al. teaches that although the effects of Myc on the expression of CD47 and PD-L1 were modest, the consequences on tumor regression were dramatic suggesting that combining a Myc inhibitor and PD-1 inhibitor could have synergistic effects. Regarding the choice of pembrolizumab as the PD-1 inhibitor for the treatment of cancer, including lung cancer, because is pembrolizumab was the first FDA approved anti-PD-1 antibody and demonstrated significant survival benefit in patients with non-small cell lung cancer compared to chemotherapy alone; see Pembrolizumab Approval Announcement. Furthermore, one would have a reasonable expectation of success in treating cancer with the combination of the Myc inhibitor of SEQ ID NO: 1 as taught by Soucek et al. and pembrolizumab because each drug can be used alone for the treatment of cancer and because Felsher et al. teaches a possible synergistic relationship when inhibitors of Myc and the PD-1/PD-L1 pathway are administered in a combination.
Moreover, regarding the combination of the Myc inhibitor of SEQ ID NO: 1 and an anti-CTLA-4 antibody, Ock et al. teaches that Myc is activated in patients who were non-responders to anti-CTLA-4 antibodies; see page 2 right column. Ock et al. continues “Myc was predicted to be negative regulator of tumor immunity. Recent study also demonstrated that MYC inhibits T-cell activation by upregulating
CD47 and PD-L1, further supporting validity of our approaches.”; see page 11 left column. Ock et al. teaches that similar to the relationship between Myc and CD47 or PD-L1 expression, Myc activation worsens response to anti-CTLA-4 antibodies. Together with the teachings of Felsher et al. indicating a relationship between Myc express and immune checkpoint expression and teaching the combined use of Myc inhibitors and immune checkpoint inhibitors, including ipilimumab, it would have been obvious and one would have had a reasonable expectation of success to treat cancer with the combination of the Myc inhibitor of SEQ ID NO: 1 and ipilimumab.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Claims 21, 30-32, 41, and 42 are rejected under 35 U.S.C. 103 as being unpatentable over Felsher et al. (WO 2017/152132 A1; Published: September 8, 2017).
Claim 21 recites a combination comprising a first component which comprises SEQ ID NO: 1 or a functionally equivalent variant and a second component comprising an anti-PD-1 or anti-CTLA-4 antibody. It is noted that the combination of claims 21-25, 30-32, 41, and 42 need not be a combination of both components into a single composition, but includes each component administered separately in a sequential manner; see page 7 of the Specification. The administration of both components together is merely intended use.
Felsher et al. teaches the method of identifying whether a subject having cancer will be responsive to an immune checkpoint inhibitor comprising determining from a sample that the cancer overexpresses a Myc oncogene, identifying the subject with Myc oncogene overexpression as responsive to immune checkpoint inhibition, and administering an immune checkpoint inhibitor, including a PD-1 inhibitor; see claims 1 and 6.
Regarding claims 21 and 32, Felsher et al. suggests that a Myc inhibitor and immune checkpoint inhibitor may be used in combination to treat cancer; see Summary on page 2. Regarding the Myc inhibitor of claim 21, Felsher et al. teaches a Myc inhibitor with the sequence of SEQ ID NO: 19, which is 100% identical to instant SEQ ID NO: 1, or a variant thereof. Regarding the immune-oncology agent of claims 21, 30, and 31, Felsher et al. teaches several PD-1/PD-L1 pathway inhibitors, including pembrolizumab, an anti-PD-1 antagonist antibody. Regarding the anti-CTLA-4 antibody of claims 1, 41, and 42, Felsher et al. teaches that the immune checkpoint inhibitor may comprise an anti-CTLA-4 antibody, including ipilimumab; see pages 14 and 36 miswritten as “CLTA4”.
Given that Felsher et al. teaches methods of administering a Myc inhibitor, including that of instant SEQ ID NO: 1, when the subject overexpresses CD47 and/or PD-L1 or of administering an immune checkpoint inhibitor, including anti-PD-1 antibodies or anti-CTLA-4 antibodies, when the subject overexpresses Myc, it would have been obvious to one of ordinary skill in the art to store both a Myc inhibitor, including that of instant SEQ ID NO: 1 and immune checkpoint inhibitor, including anti-PD-1 antibodies or anti-CTLA-4 antibodies, when practicing the methods taught by Felsher et al.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Claims 22-25 are rejected under 35 U.S.C. 103 as being unpatentable over Felsher et al. (WO 2017/152132 A1; Published: September 8, 2017) as applied to claim(s) 21, 30-32, 41, and 42 above, and further in view of Soucek et al. (WO 2014/180889 A1; Published: November 13, 2014).
The teachings of Felsher et al. as related to claim(s) 21, 30-32, 41, and 42, from which these claims depend are given previously in this Office action and are fully incorporated here.
Felsher et al. does not teach a functionally equivalent variant comprising SEQ ID NOs: 4-10, a cell penetrating peptide, nor a furth nuclear localization sequence.
Regarding claim 21, Soucek et al. teaches a combination of a polypeptide 100% identical to instant SEQ ID NO: 1 with an anti-tumoral agent; see claim 15, the translated sequence on pages 8-9, and pages 25-28.
Regarding claim 22, Soucek et al. teaches the variant called Omomyc*LZArg, which comprises SEQ ID NO: 48, on page 15. Residues 1-92 of SEQ ID NO: 48 are 100% identical to SEQ ID NO: 4.
Regarding claims 23-25, Soucek et al. claims 6-9 teach that the polypeptide or functionally equivalent variant is a fusion protein comprising a cell penetrating peptide sequence selected from SEQ ID NOs: 28 and 29, which are 100% identical to instant SEQ ID NO: 37 and 38, and further comprises a nuclear localization signal.
Given that Soucek et al. teaches the functionally equivalent variants which comprise instant SEQ ID NO: 4, a cell penetrating peptide, or a further nuclear localization signal, it would have been obvious to one of ordinary skill in the art to store a functionally equivalent variant Myc inhibitor as taught by Soucek et al. comprising SEQ ID NO: 4, a cell penetrating peptide, or a further nuclear localization signal with immune checkpoint inhibitors, including anti-PD-1 antibodies and/or anti-CTLA-4 antibodies, for the purpose of practicing the methods taught by Felsher et al.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Claims 21, 23, 25, 30, 31, 33-35, 37, 39, and 40-42 are rejected under 35 U.S.C. 103 as being unpatentable over Bidwell et al. (PLoS One. 8(1): e55104; Published: January 25, 2013) and Felsher et al. (WO 2017/152132 A1; Published: September 8, 2017) and in view of the Pembrolizumab Approval Announcement (FDA; Published: May 10, 2017) or Ock et al. (Nature Communications. 8: 1050: Published: October 19, 2017).
Regarding claim 21, Bidwell et al. teaches a therapeutic protein derived from helix 1 (H1) of the helix-loop-helix domain of c-Myc, and it functions by blocking the endogenous c-Myc/Max interaction and preventing activation of transcription by c-Myc and Max; see page 2 left column. Note that a functionally equivalent variant does not require any percent identity to instant SEQ ID NO: 1, in other words, the mutations to SEQ ID NO: 1 are limitless. Additionally, the functionally equivalent variant must substantially preserve tumor suppressor activity of SEQ ID NO: 1, but there is no guidance as to what is considered substantially preserved; see page 12 of the Specifcation. Here, Bidwell et al. teaches a therapeutic protein with a similar mechanism of action as SEQ ID NO: 1 and 13% identity to instant SEQ ID NO: 1. See the alignment below with instant SEQ ID NO: 1 in the Qy line and Bac-ELP-H1 in the Db line.
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Regarding claim 23, Bidwell et al. teaches that the therapeutic protein comprises a cell penetrating peptide sequence called Bac or SynB1; see page 5. Further, regarding claim 25, Bidwell et al. teaches that Bac targets the peptide to the cell nucleus; see page 5 right column.
Regarding claims 33 and 34, Soucek et al. teaches using the polypeptide of pharmaceutical composition comprising an anti-tumoral agent for the treatment of cancer and that lung cancer is the preferred embodiment; see claims 20 and page 16 lines 30-32.
Regarding claims 35 and 37, Bidwell et al. teaches that the Myc inhibitor is administered intravenously, or a form of systemic administration; see page 31 lines 9-13.
While Soucek et al. teaches combination regimens with the Myc inhibitor of SEQ ID NO: 1, Soucek et al. does not teach a combination or composition wherein the second component is an immune checkpoint inhibitor nor does Soucek et al. teach treating cancer with a combination or composition comprising an immune checkpoint inhibitor.
Felsher et al. teaches the method of identifying whether a subject having cancer will be responsive to an immune checkpoint inhibitor comprising determining from a sample that the cancer overexpresses a Myc oncogene, identifying the subject with Myc oncogene overexpression as responsive to immune checkpoint inhibition, and administering an immune checkpoint inhibitor, including a PD-1 inhibitor; see claims 1 and 6.
Regarding claims 21, 32, and 33, Felsher et al. suggests that a Myc inhibitor and immune checkpoint inhibitor may be used in combination to treat cancer; see Summary on page 2. Regarding the Myc inhibitor of claim 21, Felsher et al. teaches a Myc inhibitor with the sequence of SEQ ID NO: 19, which is 100% identical to instant SEQ ID NO: 1, or a variant thereof. Regarding the immune-oncology agent of claims 21, 30, and 31, Felsher et al. teaches several PD-1/PD-L1 pathway inhibitors, including pembrolizumab, an anti-PD-1 antagonist antibody. Regarding the anti-CTLA-4 antibody of claims 1, 41, and 42, Felsher et al. teaches that the immune checkpoint inhibitor may comprise an anti-CTLA-4 antibody, including ipilimumab; see pages 14 and 36 miswritten as “CLTA4”.
Regarding claims 39 and 40, the recruitment of T cells to the tumor site, the expansion of T regulatory cells, and induction of IFN-gamma are all inherent properties of claim 33. The claim requires only that a therapeutically effective amount of the combination or composition of claim 21 be administered to a subject in need thereof and no additional steps are recited. Thus, these are outcomes which would inherently flow from the administration of the combination of the polypeptide and the immune-oncology agent.
Given that Felsher et al. teaches the positive relationship between Myc expression and PD-L1 expression in human cancers, including non-small cell lung cancer, and suggests treating a subject, who has been identified as responsive to immune checkpoint inhibitors by Myc overexpression, with a Myc inhibitor and an immune checkpoint inhibitor, it would have been obvious to treat cancer using a combination of the Myc inhibitor as taught by Bidwell et al. with the anti-PD-1 antibody, pembrolizumab, as taught by Felsher et al. Additionally, Felsher et al. teaches that the Myc inhibitor of Bidwell et al. may be used; see page 33. Further, one would have been motivated to make the combination because Felsher et al. teaches that although the effects of Myc on the expression of CD47 and PD-L1 were modest, the consequences on tumor regression were dramatic suggesting that combining a Myc inhibitor and PD-1 inhibitor could have synergistic effects. Regarding the choice of pembrolizumab as the PD-1 inhibitor for the treatment of cancer, including lung cancer, because is pembrolizumab was the first FDA approved anti-PD-1 antibody and demonstrated significant survival benefit in patients with non-small cell lung cancer compared to chemotherapy alone; see Pembrolizumab Approval Announcement. Furthermore, one would have a reasonable expectation of success in treating cancer with the combination of the Myc inhibitor of as taught by Bidwell et al. and pembrolizumab because each drug can be used alone for the treatment of cancer and because Felsher et al. teaches a possible synergistic relationship when inhibitors of Myc and the PD-1/PD-L1 pathway are administered in a combination.
Moreover, regarding the combination of the Myc inhibitor and an anti-CTLA-4 antibody, Ock et al. teaches that Myc is activated in patients who were non-responders to anti-CTLA-4 antibodies; see page 2 right column. Ock et al. continues “Myc was predicted to be negative regulator of tumor immunity. Recent study also demonstrated that MYC inhibits T-cell activation by upregulating
CD47 and PD-L1, further supporting validity of our approaches.”; see page 11 left column. Ock et al. teaches that similar to the relationship between Myc and CD47 or PD-L1 expression, Myc activation worsens response to anti-CTLA-4 antibodies. Together with the teachings of Felsher et al. indicating a relationship between Myc express and immune checkpoint expression and teaching the combined use of Myc inhibitors and immune checkpoint inhibitors, including ipilimumab, it would have been obvious and one would have had a reasonable expectation of success to treat cancer with the combination of the Myc inhibitor taught by Bidwell et al. and ipilimumab.
Finally, regarding claim 34 reciting treating lung cancer, Bidwell et al. teaches that the Myc inhibitor with cell penetrating peptide accumulated in the lung (see page 7), Felsher et al. teaches treating lung cancer (see page 16), pembrolizumab was approved to treat NSCLC, and Ock et al. teaches using PD-1/PD-L1 or CTLA-4 immunotherapy in lung cancer patients (page 2 right column). Therefore, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success treating lung cancer with the combination.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
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 21-25, 30-37, 39, and 40-42 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 and 12-15 of U.S. Patent No. 10,370,434 B2 in view of Soucek et al. (WO 2014/180889 A1; Published: November 13, 2014), Felsher et al. (WO 2017/152132 A1; Published: September 8, 2017), and the Pembrolizumab Approval Announcement (FDA; Published: May 10, 2017) and Ock et al. (Nature Communications. 8: 1050: Published: October 19, 2017).
Claims 21-25, 30-37, 39, and 40-42 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 7-9, 11-13, 15, 18, 19, and 23 of U.S. Patent No. 11,339,205 B2 in view of Soucek et al. (WO 2014/180889 A1; Published: November 13, 2014), Felsher et al. (WO 2017/152132 A1; Published: September 8, 2017), and the Pembrolizumab Approval Announcement (FDA; Published: May 10, 2017) and Ock et al. (Nature Communications. 8: 1050: Published: October 19, 2017).
Claims 21-25, 30-37, 39, and 40-42 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5-11, 17-20 of U.S. Patent No. 11,427,621 B2 in view of Soucek et al. (WO 2014/180889 A1; Published: November 13, 2014), Felsher et al. (WO 2017/152132 A1; Published: September 8, 2017), and the Pembrolizumab Approval Announcement (FDA; Published: May 10, 2017) and Ock et al. (Nature Communications. 8: 1050: Published: October 19, 2017).
The following analysis applies to the nonstatutory double patenting rejections over claims U.S. Patent Nos. 10,370,434 B2; 11,339,205 B2; and 11,427,621 B2.
Regarding instant claims 21 and 32, U.S. 10,370,434 B2 teaches a combination of a polypeptide 100% identical to instant SEQ ID NO: 1 with an antitumoral agent; see issued claims 1, 2, 8, 10, 12, and 13. Similarly, U.S. 11,339,205 B2 teaches the method of treating cancer comprising administering a polypeptide comprising SEQ ID NO: 1, which is 100% identical to instant SEQ ID NO: 1, or a variant thereof in combination with an antitumoral agent; see issued claims 1, 7, 8, 11-13, 15, 18, 19, and 23. Additionally, issued claims 1-3, 17, and 18 of U.S. 11,427,621 B2 teach a functionally equivalent variant of instant SEQ ID NO: 1, which is nearly identical to instant SEQ ID NO: 1 except that the residue at position 89 may not be a cysteine. The polypeptide taught by the issued claims of U.S. 11,427,621 B2 is a functionally equivalent variant as defined on instant page 12 because it has the ability to dimerize with Myc and inhibiting its activity, translocate across the cell membrane, and translocate to the nucleus; see column 9 lines 32-38.
Regarding instant claim 22, U.S. 10,370,434 B2 teaches the variant called Omomyc*LZArg, which comprises SEQ ID NO: 48; see issued claims 7 and 12. Residues 1-92 of SEQ ID NO: 48 are 100% identical to SEQ ID NO: 4. Additionally, issued claims 18 and 23 of U.S. 11,339,205 B2 teach a variant comprising SEQ ID NO: 1, which is 100% identical to instant SEQ ID NO: 1, with a N-terminal methionine added and the resulting polypeptide is 100% identical to instant SEQ ID NO: 4. Additionally, issued claims 5 and 6 of U.S. 11,427,621 B2 teach that the polypeptide comprising SEQ ID NO: 1 has a serine or alanine at variable position 89 which is 100% identical to instant SEQ ID NO: 7 and that the polypeptide consists of SEQ ID NO: 4 which is 100% identical to instant SEQ ID NO: 6 when variable residue 90 is a serine.
Regarding instant claims 23-25, issued claims 2-6 U.S. 10,370,434 B2 teach that the polypeptide or functionally equivalent variant is a fusion protein comprising a cell penetrating peptide sequence selected from SEQ ID NOs: 28 and 29, which are 100% identical to instant SEQ ID NO: 37 and 38, and further comprises a nuclear localization signal. Issued claims 7-11 of U.S. 11,427,621 B2 teach that the polypeptide or functionally equivalent variant is a fusion protein comprising a cell penetrating peptide sequence selected from SEQ ID NOs: 38 and 39, which are 100% identical to instant SEQ ID NO: 37 and 38, and further comprises a nuclear localization signal.
Regarding instant claim 33, U.S. 10,370,434 B2 teaches using the polypeptide of pharmaceutical composition comprising an anti-tumoral agent for the treatment of cancer; see issued claims 10 and 13-15. Regarding instant claims 33 and 34, U.S. 11,339,205 B2 teaches that the combination of SEQ ID NO: 1 and an antitumoral agent is used for the treatment of cancer, including lung cancer; see issued claims 1, 2, and 13. Additionally, issued claims 19 and 20 of U.S. 11,427,621 B2 teach a method for treating cancer comprising administering the claimed polypeptide or conjugate.
Regarding instant claim 35, issued claim 9 of U.S. 11,339,205 B2 teaches that the first component, comprising SEQ ID NO: 1, is administered intranasally.
The issued claims of U.S. 10,370,434 B2 do not teach a combination or composition comprising SEQ ID NO: 1 or a variant thereof and an immune checkpoint inhibitor, including pembrolizumab, nor do the issued claims teach appropriate routes of administration or the use of the combination for the treatment of lung cancer.
The issued claims of U.S. 11,339,205 B2 do not teach a polypeptide further comprising a cell penetrating peptide or nuclear translation signal, a combination or composition comprising instant SEQ ID NO: 1 or a variant thereof and an immune checkpoint inhibitor, including pembrolizumab, nor do the issued claims teach appropriate routes of administration for each component.
The issued claims of U.S. 11,427,621 B2 do not teach a combination or composition comprising SEQ ID NO: 1 or a variant thereof and an immune checkpoint inhibitor, including pembrolizumab, nor do the issued claims teach appropriate routes of administration or the use of the combination for the treatment of lung cancer.
Similar to the issued claims of U.S. 10,370,434 B2, U.S. 11,339,205 B2, and U.S. 11,427,621 B2, Soucek et al. teaches a polypeptide 100% identical to instant SEQ ID NO: 1. Further, Soucek et al. teaches that that polypeptide may be used in combination with the immuno-oncology agent, IL-12; see claim 15, the translated sequence on pages 8-9, and page 27 lines 5.
Regarding instant claims 23-25, Soucek et al. claims 6-9 teach that the polypeptide or functionally equivalent variant is a fusion protein comprising a cell penetrating peptide sequence selected from SEQ ID NOs: 28 and 29, which are 100% identical to instant SEQ ID NO: 37 and 38, and further comprises a nuclear localization signal.
Regarding instant claim 34, Soucek et al. teaches that lung cancer is the preferred embodiment; see page 16 lines 30-32.
Regarding instant claims 35 and 36, Soucek et al. teaches intranasal administration or instillation into the nose; see page 32 lines 29-32 and page 33 lines 5-8. Further, regarding claim 37, Soucek et al. teaches that the components of the composition may be formulated differently so that the components can be differently administered and exemplifies the second component being administered intravenously, or a form of systemic administration; see page 31 lines 9-13.
While Soucek et al. teaches combination regimens with the Myc inhibitor of SEQ ID NO: 1, Soucek et al. does not teach a combination or composition wherein the second component is an immune checkpoint inhibitor nor does Soucek et al. teach treating cancer with a combination or composition comprising an immune checkpoint inhibitor.
Felsher et al. teaches the method of identifying whether a subject having cancer will be responsive to an immune checkpoint inhibitor comprising determining from a sample that the cancer overexpresses a Myc oncogene, identifying the subject with Myc oncogene overexpression as responsive to immune checkpoint inhibition, and administering an immune checkpoint inhibitor, including a PD-1 inhibitor; see claims 1 and 6.
Regarding claims 21, 32, and 33, Felsher et al. suggests that a Myc inhibitor and immune checkpoint inhibitor may be used in combination to treat cancer; see Summary on page 2. Regarding the Myc inhibitor of claim 21, Felsher et al. teaches a Myc inhibitor with the sequence of SEQ ID NO: 19, which is 100% identical to instant SEQ ID NO: 1, or a variant thereof. Regarding the immune-oncology agent of claims 21, 30, and 31, Felsher et al. teaches several PD-1/PD-L1 pathway inhibitors, including pembrolizumab, an anti-PD-1 antagonist antibody. Regarding the anti-CTLA-4 antibody of claims 1, 41, and 42, Felsher et al. teaches that the immune checkpoint inhibitor may comprise an anti-CTLA-4 antibody, including ipilimumab; see pages 14 and 36 miswritten as “CLTA4”.
Regarding claims 39 and 40, the recruitment of T cells to the tumor site, the expansion of T regulatory cells, and induction of IFN-gamma are all inherent properties of claim 33. The claim requires only that a therapeutically effective amount of the combination or composition of claim 21 be administered to a subject in need thereof and no additional steps are recited. Thus, these are outcomes which would inherently flow from the administration of the combination of the polypeptide and the immune-oncology agent.
Given that Felsher et al. teaches the positive relationship between Myc expression and PD-L1 expression in human cancers, including non-small cell lung cancer, and suggests treating a subject, who has been identified as responsive to immune checkpoint inhibitors by Myc overexpression, with a Myc inhibitor and an immune checkpoint inhibitor, it would have been obvious to treat cancer using a combination of the Myc inhibitor comprising SEQ ID NO: 1 or a variant thereof as taught by the issued claims of U.S. 10,370,434 B2, U.S. 11,339,205 B2, or U.S. 11,427,621 B2 with the anti-PD-1 antibody, pembrolizumab, as taught by Felsher et al. Further, one would have been motivated to make the combination because Felsher et al. teaches that although the effects of Myc on the expression of CD47 and PD-L1 were modest, the consequences on tumor regression were dramatic suggesting that combining a Myc inhibitor and PD-1 inhibitor could have synergistic effects. Regarding the choice of pembrolizumab as the PD-1 inhibitor for the treatment of cancer, including lung cancer, because is pembrolizumab was the first FDA approved anti-PD-1 antibody and demonstrated significant survival benefit in patients with non-small cell lung cancer compared to chemotherapy alone; see Pembrolizumab Approval Announcement. Furthermore, one would have a reasonable expectation of success in treating cancer with the combination of the Myc inhibitor of SEQ ID NO: 1 as taught by the issued claims of U.S. 10,370,434 B2, U.S. 11,339,205 B2, or U.S. 11,427,621 B2 and pembrolizumab because each drug can be used alone for the treatment of cancer, because Soucek et al. teaches that the same polypeptide or a functionally active variant thereof can be used in combination with an immune-oncology agent, and because Felsher et al. teaches a possible synergistic relationship when inhibitors of Myc and the PD-1/PD-L1 pathway are administered in a combination.
Moreover, regarding the combination of the Myc inhibitor of instant SEQ ID NO: 1 and an anti-CTLA-4 antibody, Ock et al. teaches that Myc is activated in patients who were non-responders to anti-CTLA-4 antibodies; see page 2 right column. Ock et al. continues “Myc was predicted to be negative regulator of tumor immunity. Recent study also demonstrated that MYC inhibits T-cell activation by upregulating CD47 and PD-L1, further supporting validity of our approaches.”; see page 11 left column. Ock et al. teaches that similar to the relationship between Myc and CD47 or PD-L1 expression, Myc activation worsens response to anti-CTLA-4 antibodies. Together with the teachings of Felsher et al. indicating a relationship between Myc express and immune checkpoint expression and teaching the combined use of Myc inhibitors and immune checkpoint inhibitors, including ipilimumab, it would have been obvious and one would have had a reasonable expectation of success to treat cancer with the combination of the Myc inhibitor of instant SEQ ID NO: 1 as taught by the issued claims and ipilimumab.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Response to Arguments
Applicant’s amendments filed April 16, 2026 are acknowledged. Any rejection not repeated above is resolved by amendment.
Applicant argues unexpected results when the Myc inhibitor comprising SEQ ID NO: 4 (as evidenced by the example titled ‘Production and purification of Omomyc’) is administered in combination with an anti-PD-1 or anti-CTLA-4 antibody.
While Felsher et al. might suggest a possible synergy between Myc inhibitors and immune checkpoint inhibitors, there is no reduction to practice administering these two agents in vivo or applying them in combination in vitro. The reference suggests benefit based on changes in expression of CD47 and PD-L1 following Myc inhibition.
First, Applicant points to elevated production of IFN-gamma; see page 6 of the arguments. Indeed, Figure 4B demonstrates increased IFN-gamma expression among CD8 cells with a mean percent CD8+IFN+ cells following combined Omomyc and anti-PD-1 antibody treatment appearing to be greater than the mean percent CD8+IFN+ cells following each Omomyc or anti-PD-1 antibody treatment alone.
Second, Applicant points to increased T cell recruitment following combined Omomyc and anti-PD-1 antibody treatment. Interestingly, combination treatment increased the proportion of CD4+ or CD8+ T cells co-expressing PD-1 and the proportion of CD4+PD-1+Tim3+ cells to an extent which is more than merely additive; see Tables 3-5. Similarly, combination treatment with Omomyc and an anti-CTLA-4 antibody demonstrated synergic increases in proportion of CD4+ or CD8+ T cells co-expressing PD-1 and the proportion of CD4+PD-1+Tim3+ cells; see Figures 6 and 7.
MPEP 716.02(d) states that the unexpected results must commensurate in scope with the claimed invention.
Regarding claims 21-25, 30-32, 41, and 42 drawn to a combination or composition, the claims suffer from the following deficiencies:
The Myc inhibitor component comprises functionally equivalent variants, which is extensively broad. According to page 12, there is no requirement of minimal percent identity to SEQ ID NO: 1, just that alterations with respect to SEQ ID NO: 1 “substantially preserve tumor suppressor activity”; see page 12. To what degree must suppressor activity be “substantially preserved” in order for the variant to also achieve unexpected results? In contrast to this breadth, the examples appear to be treating with only the Myc inhibitor of SEQ ID NO: 4; see page 73.
These claims are drawn to products, yet administering the Myc inhibitor and anti-PD-1 antibody or anti-CTLA-4 antibody are required to achieve the unexpected results. Additionally, the combination as defined on page 7 of the Specification includes both sequential administration and single formulations. In contrast, the unexpected results were demonstrated with sequential administration.
In addition to the above, claims 33-37, 39, and 40 drawn to the method of treating cancer suffer from the following deficiencies:
The claims are drawn to the method of treating any cancer. The experiments through which unexpected results were demonstrated are in KRAS-mutated, p53-mutated lung cancer.
All rejections were updated as necessitated by amendment and all rejections are maintained as the unexpected results are not commensurate in scope with the claimed invention.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure: Soucek et al. (Oncogene. 17: 2463-2472; Published: October 12, 1998) teaches OmoMyc variants and suggests the use of such variants for the treatment of cancer. Wang et al. (Oncogene. 38: 140-150; Published: August 3, 2018) teaches OmoMyc having the sequence identical to SEQ ID NO: 1 and suggests combining with chemotherapy for the treatment of cancer. Annibali et al. (Nature Communications. 5: 4632; Published: August 18, 2014) teaches OmoMyc as a possible treatment for glioma. Casey et al. (Science. 352(6282): 227-231; Published: March 10, 2016) teaches that Myc regulates the expression of CD47 and PD-L1. Kim et al. (Lung Cancer. 110: 63-67; Published: June 20, 2017) teaches the correlation between Myc and PD-L1 expression in non-small cell lung cancer.
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/KATHERINE ANN HOLTZMAN/Examiner, Art Unit 1646
/JULIET C SWITZER/Primary Examiner, Art Unit 1682
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