Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 7-30-26 has been entered.
Claims 42-44, 49, 74-77, 84-99 are pending and under examination as they read on the species of invention of Group I wherein the immunomodulatory compound is “a cytokine” and wherein the sub-species of cytokine is “GM-CSF or IL-12.”
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The prior rejection over claims 1-12 of U.S. Patent No. 11033613 has been withdrawn upon reconsideration. In particular, it is no longer clear to the undersigned how the reference claim could be said to render the instant claims obvious when the reference claims fail to recite SEQ ID NOs: 41 or 42.
Applicant’s submission of an IDS on 7-8-26 is acknowledged.
The EP examination report cited therein points to the teachings of Gaiger et al. (WO0228414A2), Kobayashi et al. (Cancer Immunol Immunother (2006) 55: 850–860) and Scheinberg et al. (WO2005053618)(all cited on a prior IDS), and describes various teachings from these references that are of relevance to the claimed invention.
Among these various references it is the opinion of the undersigned that the teachings of Kobayashi were the most relevant to claims 74 and dependent claims thereof. Moreover, prompted in part by the reasoning set forth in the EP examination report, the undersigned considered a potential prima facie case of obviousness over the teachings of Kobayashi in view of Gao et al. (Blood. 2000;95:2198-2203, cited herewith) and Scheinberg et al. (20100111986, cited on an IDS) as described below.
Kobayashi taught two peptides, WT1124–138 and WT1247–261, which, “…were shown to induce peptide-specific HTL, which were restricted by frequently expressed HLA class II alleles,” wherein said peptides have an advantageous feature: “Interestingly, the two WT1 HTL epitopes described here are closely situated to known MHC class I-restricted CTL epitopes, raising the possibility of stimulating CTL and HTL responses using a relatively small synthetic peptide vaccine.” (see Abstract, emphasis added).
The final sentence of the Introduction of Kobayashi taught: “These WT1 HTL epitopes could be used in combination with the previously described CTL epitopes to increase the immunological responses of WT1-peptide vaccine than using only MHC class I-restricted CTL epitope peptide in clinical setting.”
With respect to the overlap of class I and II epitopes in their peptides Kobayashi further taught at page 852 column bridging paragraph:
“When examining the position that these peptides occupy within the WT1 molecules, it became evident that several of these peptides were proximal to or overlapped with recently described MHC class I-restricted CTL epitopes. Specifically, WT1247–261 is proximal to the HLA-A24-restricted CTL epitope, WT1235–243 and WT1124–138 overlaps with the HLA-A2-restricted CTL epitope, WT1126–134[10–13].”
At page 853 final full paragraph Kobayashi describes how helper T cells selected for their ability to recognize the WT1124–138 and WT1247–261 peptides are capable of lysing WT-1 expressing tumor cells:
“The data presented above demonstrated that the peptides WT1124–138 and WT1247–261 were indeed capable of inducing CD4+ T-cell responses. However, in order to assume these TAA, peptide-epitopes will be useful for the design of cancer immunotherapy, these peptides need to be processed endogenously or exogenously by APC and/or WT1+ tumor cells that express MHC class II molecules. Thus, we examined the ability of peptide induced HTL to directly recognize tumor cells that express both WT1 protein and cell surface HLA-DR molecules. We assumed that EBV-LCL should be good targets for recognition assays by peptide-reactive HTL because these cells express the WT1 protein and high levels of MHC class II molecules (without requiring IFN-γ treatment to enhance surface MHC expression). Therefore, we first used EBV-LCL as targets to assess direct recognition by the peptide-reactive HTL lines.”
Results from the above described experiments were presented in Kobayashi Figs. 5-6.
The first paragraph of the Discussion section taught:
“WT1 seems to be one of the most ideal TAA for cancer immunotherapy since there is accumulating evidence that WT1 is overexpressed in most leukemias and various epithelial solid tumors [2–6]. Thus, several groups have been identified the potent immunogenic peptides of WT1 for HLA-A2 and HLA-A24 that could elicit efficient CTL that exhibited cytotoxic activity against WT1-positive tumor cells in vitro [10–13]….
Although CTL are the most effective immune elements for eradicating tumor cells, HTL also play a critical role in the generation and maintenance of CTL anti-tumor responses. Therefore, we believe that a vaccine should contain not only CTL epitopes but also HTL epitopes to develop an effective anti-tumor immune response….
Furthermore, it is significant that the two HTL epitopes, WT1124–138 and WT1247–261 are found in close proximity to two CTL epitopes: WT1126–134 (HLA-A2-restricted) and WT1235–243 (HLAA24-restricted). Thus, it would be possible to stimulate both CTL and HTL, utilizing a relatively short peptide.”
Note that the WT1124–138 epitope of Kobayashi corresponds to the WT1 peptide of “QARMFPNAPYLPSCL” while the WT1126–134 epitope of Kobayashi corresponds to the WT1 peptide of “RMFPNAPYL” (emphasis added)(see, e.g., Scheinberg et al., 20100111986, cited on an IDS, SEQ ID NO: 50 at paragraph 0028 referring to the prior art WT1 sequence found in GenBank Accession number AY245105 which provides the sequence for the WT1124–138 and WT1126–134 epitopes).
However, Kobayashi fails to teach the nucleic acid molecule encoding the isolated peptide QAYMFPNAPYLPSCL recited in claim 74 and dependent claims thereof.
With respect to the WT1126–134 epitope of Kobayashi which corresponds to the WT1 peptide of “RMFPNAPYL,” Gao et al. teaches CTL selected for their ability to recognize the WT1 “P126” peptide RMFPNAPYL with high avidity (see Blood. 2000;95:2198-2203, cited herewith, at page 2200, left col., last full paragraph; see also Fig. 1 and associated text) were capable of lysing CD34+ cells purified from patients with leukemia (see page 2201-2 bridging paragraph and Fig. 3).
At page 2203 right col., 1st full paragraph Gao concludes, “In addition, it is possible that WT1 can be exploited for antigen-specific therapy in the autologous setting. This is supported by our observation that P126-specific CTL can be isolated from HLA-A02011 donors (unpublished data). Because WT1 expression in adults is restricted to a relatively small number of cells (eg, CD341 bone marrow cells, renal podocytes, testicular Sertoli cells, and ovarian granulosa cells), tolerance of autologous T lymphocytes to WT1 is probably incomplete. Therefore, it may be possible to exploit the identified P126 epitope for the design of anti-WT1 vaccine preparations aimed at stimulating CTL responses against leukemia and other malignancies with elevated WT1 expression, such as renal cell carcinoma, ovarian cancer, melanoma, and breast cancer.” (emphasis added)
Furthermore, at Figs. 3A Scheinberg et al. (20100111986) shows CD8+ T-cells (CTLs) isolated from a donor via stimulation with the heteroclitic WT1 peptide of “YMFPNAPYL” (see Table 1) are more potently activated by T2 cells presenting the native WT1 equivalent peptide “RMFPNAPYL” than are CTLs isolated from a donor via stimulation with the native WT1 equivalent peptide “RMFPNAPYL.” (see Fig. 3A).
Said findings are summarized by Scheinberg at paragraphs 242-43 as follows:
“[0242] To determine the ability of heteroclitic WT1 peptides to generate immune responses against native and heteroclitic WT peptides, the CD3+ PBMC subpopulation of a healthy donor was isolated and stimulated with autologous monocyte-derived, peptide-pulsed DC, then re-stimulated with peptide-pulsed CD14+ monocytes. The presence of activated, antigen-specific T cells was then determined using pulsed, HLA-matched leukemic cell lines. Several analogue peptides generated greater immune responses (i.e. increased T cell precursor frequency, in comparison with the native peptides) by IFN, gamma ELISPOT (FIG. 2A) and chromium release assay (FIG. 2B). Similar results were observed using CD3+ (FIGS. 3B-D) and CD8+ (FIG. 3A) subpopulations of donors. Moreover, CD8+ T cells stimulated with the heteroclitic WT1 peptides cross-reacted with the native WT1 peptides and were able to lyse HLA-matched CML blasts (FIGS. 4A-B).
[0243] Thus, heteroclitic WT1 peptides of the present invention are able to generate T cells that (a) secrete inflammatory cytokines and (b) perform cytolysis in response to cells presenting WT1 peptides. In addition, the T cells generated by the heteroclitic WT1 peptides recognize both native and heteroclitic WT1 peptides.”
The above reference teachings raise the following question: given the teachings of Kobayashi, Gao and Scheinberg, would it would have been obvious to one of ordinary skill in the art to modify the WT1124–138 epitope of Kobayashi (“QARMFPNAPYLPSCL”) by substitution of the Arg at position 3 with a Tyr to generate a “heteroclitic” MHC class I epitope within the WT1124–138 epitope of Kobayashi?
It is the opinion of the undersigned that it would not have been prima facie obvious to do so.
The primary reason it would not have been obvious to modify the WT1124–138 epitope of Kobayashi (“QARMFPNAPYLPSCL”) by substitution of the Arg at position 3 with a Tyr to generate a “heteroclitic” MHC class I epitope within the WT1124–138 epitope of Kobayashi was because such a modification would change the MHC class II core epitope peptide flanking residue at position “P-1” from Arg to Tyr; however, as described by Rudolph at page 421-23 bridging paragraph, “…in MHC class II, the termini, particularly the N-terminal extension (P-4 to P-1), can play a major role in the TCR interaction.” (see Rudolph et al., Annu Rev Immunol. 2006;24:419-66, cited herewith). Thus, the ordinarily skilled artisan would have more likely than not refrained from attempting to modify the WT1124–138 epitope of Kobayashi by substitution of the Arg at position 3 with a Tyr to generate a “heteroclitic” MHC class I epitope (see Scheinberg) within the context of the larger WT1124–138 epitope for fear that such a substitution may have a substantially unfavorable effect on the immunogenicity of the class II the WT1124–138 epitope of Kobayashi. Notably, the idea of flanking residues being important for MHC class II epitopes was also taught by Fikes at paragraphs 199 and 370.
Given the above it is the opinion of the undersigned that the ordinarily skilled artisan would be more inclined to combine the heteroclitic MHC class I epitope of Scheinberg in the context of a multiepitope vaccine as opposed to modifying the WT1124–138 epitope of Kobayashi to substitute the Arg at position 3 with a Tyr.
With respect to the teachings of Gaiger, the peptide containing residues 117-134 of WT1 (see page 15-16 bridging paragraph corresponding to SEQ ID NOs: 2 and 3 of Gaiger) includes all of instant SEQ ID NO: 41 in its breadth but lacks the C-terminal Ser residue contained within SEQ ID NO: 41. Given this difference it is unclear how this reference could serve as the basis for an obviousness rejection (even when combined with the other reference teachings set forth above); moreover, this combination of references would also not adequately address the concerns associated with modification of the MHC class II core epitope peptide flanking residue at position “P-1” from Arg to Tyr.
Claims 42-44, 49, 74-77 and 84-99 stand rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-12 of U.S. Patent No. 11033613 (hereinafter the “613”), in view of Fikes et al. (20040053822) and Iversen (20020025939)(all of record).
Applicant asserts the following:
“Applicant respectfully submits that it is not arguing that the instant application is a
divisional application of the '613 patent or that it is entitled to safe harbor protection. Rather,
Applicant submits that in both the instant application and the application leading to the '613
patent, the Office has stated that nucleic acids and vectors, vaccines and compositions
comprising nucleic acids are distinct inventions -i.e., novel and non-obvious-from
therapeutic methods using peptides or nucleic acids.
The instant claims directed to nucleic acid molecules encoding peptides, and vaccines, vectors and compositions comprising them are patentably distinct from the methods of treatment using peptides as recited in the '613 patent. First, the invention of the instant claims and those of the claims of the '613 patent are directed to an unrelated product and process. This, the Office has indicated, renders inventions patentably distinct. See US 16/359,897 (from which the instant application claims benefit), October 13, 2021, Restriction Requirement, pp. 3. Additionally, the process of the claims of the '613 patent is practiced with a product that is materially different from that of the instant claims. Again, the Office has indicated that this renders inventions patentably distinct. Id. p. 3.”
Applicant's argument has been considered but has not been found convincing essentially for the reasons of record as described below.
If, as applicant asserts, the instant application is not a divisional application of the '613 patent nor is it entitled to safe harbor protection, then why are the obviousness-type double patenting rejections not valid?
Applicant continues their argument by asserting that “…in both the instant application and the application leading to the '613 patent, the Office has stated that nucleic acids and vectors, vaccines and compositions comprising nucleic acids are distinct inventions -i.e., novel and non-obvious-from therapeutic methods using peptides or nucleic acids,” and concludes “[t]he instant claims directed to nucleic acid molecules encoding peptides, and vaccines, vectors and compositions comprising them are patentably distinct from the methods of treatment using peptides as recited in the '613 patent.”
However, with respect to the restriction requirements in both the instant application and in the application that lead to the ‘613 patent, it is the examiner’s position that the distinction between products and (processes of using said products) are only applicable for the claims of the particular application in question, i.e., the 3-6-25 restriction requirement set forth in the instant application segregating the claims into groups I and II applies to the claims that were considered for the 3-6-25 restriction requirement; likewise the 1-10-20 restriction requirement set forth in the 15/777,514 application (which lead to the ‘613 patent) segregating the claims into groups I and II applies to the claims that were considered for the 1-10-20 restriction requirement.
As to applicant’s assertion that “…the process of the claims of the '613 patent is practiced with a product that is materially different from that of the instant claims,” it does appear that the methods of treatment of the ‘613 patent are substantially different from methods that do not require, e.g., administration of a checkpoint inhibitor.
That said, in practicing the reference methods of treatment it would be obvious to the ordinarily skilled artisan to produce the nucleic acids of the instant claims and for this reason in practicing the reference methods of treatment the ordinarily skilled artisan will necessarily be in possession of the nucleic acids / vectors / pharmaceutical compositions / vaccines recited in the instant claims.
With respect to applicant’s assertion that “…the instant application does not involve an unjust timewise extension over the '613 patent. MPEP § 804 requires that the Examiner determine whether the grant of a second patent would give rise to an unjustified extension of the rights granted in the first patent. In the instant case, there is no timewise extension as the instant application has an earlier effective filing date than the '613 patent.”
The precedential decision of Ex parte NICOLAS BAURIN that was issued 8-6-26 by the Appeals Review Panel (“ARP”) of the Patent Trial and Appeal Board, pages 1-34, cited herewith, is instructive.
“Improper term extension, however, is not the only rationale underpinning the OTDP doctrine. As discussed above, the anti-harassment rationale is a second justification for the doctrine. As the Federal Circuit has recognized:
There are two justifications for obviousness-type double patenting. The first is ‘to prevent unjustified timewise extension of the right to exclude granted by a patent no matter how the extension is brought about.’ Van Ornum, 686 F.2d at 943–44 (quotation and citation omitted). The second rationale is to prevent multiple infringement suits by different assignees asserting essentially the same patented invention. Fallaux, 564 F.3d at 1319 (recognizing that ‘harassment by multiple assignees’ provides ‘a second justification for obviousness-type double patenting’); see also Chisum on Patents § 9.04[2][b][ii] (‘The possibility of multiple suits against an infringer by assignees of related patents has long been recognized as one of the concerns behind the doctrine of double patenting.’).
In re Hubbell, 709 F.3d 1140, 1145 (Fed. Cir. 2013).
Current Office guidance instructs examiners to consider both rationales when making OTDP rejections. See MPEP § 804(II)(B). As spelled out in that guidance, ‘[a] rejection based on nonstatutory double patenting is based on a judicially created doctrine grounded in public policy so as to prevent the unjustified or improper timewise extension of the right to exclude granted by a patent.’ Id. (citing precedents). Moreover, the guidance states, ‘[a] double patenting rejection also serves public policy interests by preventing the possibility of multiple suits against an accused infringer by different assignees of patents claiming patentably indistinct variations of the same invention.’ Id. (citing precedents)…..
If, contrary to our conclusion here, the Federal Circuit’s precedents should not be read as permitting OTDP rejections based on the antiharassment rationale where no term-extension concern is apparent, the Office would welcome that clarification from the court. Indeed, the issue is now before the court in In re: Ablynx N.V., Appeal No. 26–1333 (sub nom Ex parte Baumeister). See Ex parte Baumeister, 2025 WL 3515282 at *10 (PTAB Nov. 20, 2025) (determining that Van Ornum, Fallaux, and related progeny supported the examiner’s OTDP rejection, and rejecting appellant’s argument that those precedents were ‘wrongly decided’ because the ‘Board is not the proper venue to address this argument’); see also id. at *5 (determining that ‘Fallaux remains good law’ and rejecting appellant’s argument ‘that the reference patents do not qualify as [OTDP] references because they each have a later patent term filing date compared to the instant application and expires later than any patent issuing from the instant application’).”
Thus, even if the grant of a second patent would not give rise to an unjustified extension of the rights granted in the ‘613 patent, at this time the patent office continues to operate under the guidance set forth in the MPEP which, consistent with the precedential decision of Ex parte NICOLAS BAURIN, instructs examiners to consider both rationales when making OTDP rejections. See MPEP § 804(II)(B).
As spelled out in that guidance, “’[a] rejection based on nonstatutory double patenting is based on a judicially created doctrine grounded in public policy so as to prevent the unjustified or improper timewise extension of the right to exclude granted by a patent.’ Id. (citing precedents),” that said, the guidance further specifies, “‘[a] double patenting rejection also serves public policy interests by preventing the possibility of multiple suits against an accused infringer by different assignees of patents claiming patentably indistinct variations of the same invention.’ Id. (citing precedents).” (emphasis added)
To provide an example of the latter rationale, insofar as the patent upon which the ODP rejection is based were to be differently assigned relative to a second party, and the instant application (should it also issue as a patent) continue to be assigned to Memorial Sloan Kettering Cancer Center (MSKCC), then some third party practicing the reference claims could be simultaneously sued by both MSKCC and said second party. Such a scenario would be akin to multiple suits against an accused infringer by different assignees of patents claiming patentably indistinct variations of the same invention.
All that said, applicant is reminded that section 1701 of the MPEP expressly indicates that Office personnel may not express an opinion regarding the expiration date of any patent. Moreover, the Office cannot predict the expiration date of any patent that may issue from an application because both patent term adjustment (PTA) and patent term extension (PTE) must be calculated after issuance. Thus, the office cannot know and further will not speculate on the expiration date of a patent which may issue from the instant application, said prospective patent which may or may not expire prior to the 11-18-2036 expiration date of the ‘613 reference patent.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZACHARY S SKELDING whose telephone number is (571)272-9033. The examiner can normally be reached M-F 9-5 EST.
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/ZACHARY S SKELDING/Primary Examiner, Art Unit 1644
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