Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Election/Restrictions
Applicant’s election without traverse of the required species in the reply filed on 2/5/25 is acknowledged.
Claims 25 and 27 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 2/5/25.
Claims 20-24, 26 and 28-35 are examined on the merits and no claims are allowable.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
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 seg. for applications not subject to examination under the first inventor to file provisions of the AJA. 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.
(Prior Rejection Maintained) Claims 20-24, 26 and 28-35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 and 6-24 of U.S. Patent No. 11,065,329. Although the claims at issue are not identical, they are not patentably distinct from each other because both the patented invention and the instant invention are drawn to variants of a protein comprising amino acid sequences of a plurality of CTL epitopes, wherein at least two of the CTL epitopes are separated by a sequence consisting of an intervening amino acid sequence, wherein the intervening amino acid sequence is a one or two amino acid sequence that comprises a proteasome liberation amino acid sequence selected from AD, K and R, and wherein the protein is capable of eliciting a cytotoxic T-lymphocyte immune response upon administration to an animal as an exogenous protein. The patented invention also requires that a Transporter Associated with Antigen Processing recognition motif is optionally present in the protein.
Both inventions also require EBV CTL epitopes derived from the same antigens, nucleic acid sequences encoding the protein, an adenovirus comprising the nucleic acid and a pharmaceutical composition comprising the protein.
Response to arguments:
Applicant presents the following arguments in traversal of the rejection:
The patented invention is drawn to a composition while the instant invention is drawn to a method of inducing or eliciting cytotoxic T-lymphocyte immune responses. Therefore the inventions are distinct.
In response, as stated above and in the previous Office action, the patented invention includes a wherein clause that states “wherein the protein is capable of eliciting a cytotoxic T-lymphocyte immune response upon administration to an animal as an exogenous protein.” [see claim 1, lines 8-10] Additionally, the patented invention requires a pharmaceutical composition comprising the protein of claim 1, which implies in vivo applications. Therefore, the patented invention is drawn a composition intended for administration to a host for eliciting a cytotoxic T-lymphocyte immune response, much like the instant invention.
(Prior Rejection Maintained) Claims 20-24, 26 and 28-35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 9,901,632. Although the claims at issue are not identical, they are not patentably distinct from each other because both the patented invention and the instant invention are drawn to variants of the a protein comprising amino acid sequences of a plurality of CTL epitopes, wherein at least two of the CTL epitopes are separated by a sequence consisting of an intervening amino acid sequence, wherein the intervening amino acid sequence is a one or two amino acid sequence that comprises a proteasome liberation amino acid sequence selected from AD, K and R, and wherein the protein is capable of eliciting a cytotoxic T-lymphocyte immune response upon administration to an animal as an exogenous protein. The patented invention also requires that a Transporter Associated with Antigen Processing recognition motif is optionally present in the protein.
Both inventions also require EBV CTL epitopes derived from the same antigens, nucleic acid sequences encoding the protein, an adenovirus comprising the nucleic acid and a pharmaceutical composition comprising the protein.
Response to arguments:
Applicant presents the following arguments in traversal of the rejection:
The patented invention is drawn to a composition while the instant invention is drawn to a method of inducing or eliciting cytotoxic T-lymphocyte immune responses. Therefore the inventions are distinct.
In response, as stated above and in the previous Office action, the patented invention includes a wherein clause that states “which is a vaccine for eliciting a cytotoxic T-lymphocyte (CTL) immune response in an animal.” [see claim 15] Additionally, the patented invention requires a pharmaceutical composition comprising the protein of claim 1, which implies in vivo applications. Therefore, the patented invention is drawn a composition intended for administration to a host for eliciting a cytotoxic T-lymphocyte immune response, much like the instant invention.
(Prior Rejection Maintained) Claims 20-24, 26 and 28-35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 11,896,665. Although the claims at issue are not identical, they are not patentably distinct from each other because both the patented invention and the instant invention are drawn to variants of a protein comprising amino acid sequences of a plurality of CTL epitopes, wherein at least two of the CTL epitopes are separated by a sequence consisting of an intervening amino acid sequence, wherein the intervening amino acid sequence is a one or two amino acid sequence that comprises a proteasome liberation amino acid sequence selected from AD, K and R, and wherein the protein is capable of eliciting a cytotoxic T-lymphocyte immune response upon administration to an animal as an exogenous protein. The patented invention also requires that a Transporter Associated with Antigen Processing recognition motif is optionally present in the protein.
Both inventions also require EBV CTL epitopes derived from the same antigens, nucleic acid sequences encoding the protein, an adenovirus comprising the nucleic acid and a pharmaceutical composition comprising the protein.
Response to arguments:
Applicant presents the following arguments in traversal of the rejection:
The patented invention is drawn to a composition while the instant invention is drawn to a method of inducing or eliciting cytotoxic T-lymphocyte immune responses. Therefore the inventions are distinct.
In response, as stated above and in the previous Office action, the patented invention includes a wherein clause that states “wherein the protein is capable of eliciting a cytotoxic T-lymphocyte immune response upon administration to an animal as an exogenous protein.” [see claim 1, lines 7-10] Additionally, the patented invention requires a pharmaceutical composition comprising the protein of claim 1, which implies in vivo applications. Therefore, the patented invention is drawn a composition intended for administration to a host for eliciting a cytotoxic T-lymphocyte immune response, much like the instant invention.
Claim Rejections - 35 USC § 102
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-AJA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis 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.
The following is a quotation of the appropriate paragraphs of pre-AIA 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 —
(b) the invention was patented or described in a printed publication in this or a foreign country or in public use or on sale in this country, more than one year prior to the date of application for patent in the United States.
(Prior Rejection Maintained) Claims 20-24, 26, 30-31, 33-35 are rejected under pre-AIA 35 U.S.C. 102b as being anticipated by Steinman and Muenz (US PGPub 2006/0188520) and evidenced by Genbank Accession YP_401677 (2010).
Steinman and Muenz teach the formulation of an Epstein Barr Virus (EBV) composition that comprises a purified EBNA-1 protein and the administration of these protein in order to elicit immune responses. [see abstract and claim 10] While Steinman and Muenz do not state that proteasome liberation amino acids are present in the sequence of the EBNA-1 protein, the specification of the instant invention states that these amino acids are AD, K and/or R. As evidenced by Genbank Accession YP_401677, EBV EBNA-1 proteins already possess these liberation amino acids. Steinman and Muenz also teach that CTL epitopes of the EBNA-1 protein are important with regard to eliciting a cell-mediated immune response. [see abstract and paragraphs 7, 9 and 27] Upon administration, the EBNA-1 polypeptide inherently undergoes processing in order for CTL epitopes to be presented, therefore the polypeptide contains a Transporter Associated with Antigen Processing recognition motif. It is also taught that nucleic acid sequences encoding the EBNA-1 and its CTL epitopes are integrated into an expression vector. [see paragraph 11] Steinman and Muenz also teach that recombinant expression vectors, such as adenoviruses, can be used to express CTL epitopes [see paragraph 75, 79 and 80] and nucleic constructs that encode the CTL epitopes, and a pharmaceutical composition comprising EBV [see paragraphs 52 and 53] and pharmaceutical carriers and adjuvants [see paragraphs 96 and 97].
Therefore, Steinman and Muenz anticipate the instant invention.
Response to arguments:
Applicant presents the following arguments in traversal of the rejection:
While Steinman and Muenz may not deliberately insert the AD, K or R amino acids between CTL epitopes of their EBNA-1 protein, as stated above and previously, the structure of this protein inherently possesses such amino acids between CTL epitopes. Moreover, the claims do not require the insertion of the AD, K or R amino acids, rather, the protein administered merely has to possess the amino acids. In addition, the claimed invention does not require that CTL epitopes from EBV and CMV be present in the protein, therefore, applicants are arguing a limitation not claimed. While Steinman and Muenz may contemplate one pathway of immune response targeting, the protein administered by Steinman and Muenz possesses the same structure as what is claimed and therefore, the administration of their EBNA-1 protein would inherently elicit an immune response that includes cytotoxic T-lymphocytes as well as CD4 T-cells.
Claim Rejections - 35 USC § 103
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-AJA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis 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.
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre- AJA 35 U.S.C. 103(c) and potential pre-ATA 35 U.S.C. 102(e), (D or (g) prior art under pre-AJA 35 U.S.C. 103(a).
(Prior Rejection Maintained) Claims 28 and 29 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Steinman and Muenz and GenBank Accession YP_401677 as applied to claims 20-24, 26, 30-31, 33-35 above, and further in view of Moss et al. (WO/95/24925) and Khanna et al. (US PGPub 2002/0150590).
The teachings of Steinman and Muenz and YP_401677 are discussed above, however, they do not specifically teach that at least one epitope is restricted to HLA-A2 and the protein comprises SEQ ID NO: 27.
Moss et al. teach CTL epitopes of EBV viruses, such as a protein that comprises SEQ ID NO: 27. [see page 2]
Khanna et al. teach several different EBV epitopes with some totaling 19 different sequences, such as those disclosed in paragraphs 7-9.
It would have been obvious to one of ordinary skill in the art to modify the composition taught by Steinman and Muenz in order to utilize the CTL epitope of SEQ ID NO: 27 as part of immunogenic protein. One would have been motivated to do so, given the suggestion by Steinman and Muenz that CTL epitopes of EBV proteins, such as EBNA-1 are of important pursuit in order to improve cell mediated immune responses against the virus and that HLA restriction is also a consideration. There would have been a reasonable expectation of success, given the knowledge that the epitope of SEQ ID NO: 27 was previously known in a EBV
EBNA-1 protein, as taught by Moss et al, and also given the knowledge that several EBV CTL epitopes, some of which amount to 19 different epitopes, as taught by Khanna et al. Thus the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Response to arguments:
Applicant presents the following arguments in traversal of the rejection:
First, none of the cited references, alone or in combination, teach or suggest a method of inducing a cytotoxic T-lymphocyte immune response by administering a synthetic polyepitope protein comprising multiple CTL epitopes separated by intervening amino acid sequences consisting of proteasome liberation residues (AD, K, or R) and optionally TAP recognition motifs. Steinman and Muenz disclose full- length EBNA-1 protein or nucleic acids encoding EBNA-1, not a rationally engineered polyepitope construct. Moss and Khanna identify individual EBV epitopes but do not teach combining them into a single protein with engineered linkers to optimize proteasomal processing and MHC-I presentation.
Third, the present application provides compelling experimental evidence of unexpected technical benefits. Specifically the claim polypeptides increase IFN-gamma expression, which is a marker for cytotoxic activity, when the polyepitope protein comprises a proteasome liberation sequence, a TAP recognition motif sequence or combination thereof, which induce higher levels of IFN-gamma. Figures 5 and 6 show that specific polyepitope proteins show processing and presentation through use of proteasome liberation sequence and mice receiving a CMVpoly epitope protein with a liberation sequence induced higher frequences of CD8+ T cells compared to mice immunized with CMV. Lastly, the claimed invention is not a mere aggregation of known epitopes. It is a novel method comprising rationally designed polyepitope constructs that incorporate multiple CTL epitopes from EBV and/or CMV for broad HLA coverage; utilizes engineered proteasome liberation sequences and TAP motifs to cover EBNA-1s natural processing limitations; and demonstrates unexpected immunological performance, including TAP-independent proteasome/autophagy dependent processing.
In response, it is acknowledged that the teachings of Steinman and Muenz do not teach that at least one epitope is restricted to HLA-A2 and the protein comprises SEQ ID NO: 27. However, the method of claim 20 recites the administration of “a protein comprising amino acid sequence of a plurality of CTL epitopes” and at least two of the epitopes are separated by the proteasome liberation amino acids AD, K or R and optionally a TAP recognition motif sequence. Claims 23, 24 and 26 require that at least one epitope if derived from an EBV EBNA-1 protein.
Therefore, based on the broadest reasonable interpretation, prior art such as Steinman an Muenz, which teach administering an EBNA-1 protein would teach the method of at least claim 20. The EBNA-1 protein of Steinman and Muenz possesses the claimed liberation amino acids, as evidenced by a Genbank Accession YP_401677 [residues 412 and 413 possess AD and several instances of arginines and lysines-see shaded residues in sequences provided below].
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Steinman and Muenz also teach that CTL epitopes of the EBNA-1 protein are important with regard to eliciting a cell-mediated immune response. [see abstract and paragraphs 7, 9 and 27]
Second, EBNA-1 possesses a glycine-alanine repeat region that is known to impair proteasomal degradation and MHC-1 presentation, making it a poorly suited for CD8+ activation.
In response, Steinman and Muenz teach that during an EBV infection, EBNA-1 is invisible to CD8+ T cells due to the gagaga… repeat domain of EBNA-1 [see paragraph 26 of Steinman and Muenz]. However, dendritic cells manipulated to present EBNA-1 epitopes were capable of eliciting CD4+ T helper cells in vitro and IFN-gamma production was detected [see vvEBNA-1 column in Table 1 presented below], indicating that CD8 + T cells activation pathways were elicited. [see working example 1 of Steinman and Muenz and Table 1 presented below] Furthermore, the claimed invention does not specify if the CTL response is that of CD4+ T cells or CD8+ T cells and Steinman and Muenz refer to CD4+ and CD8+ T cells as both being cytotoxic. [see paragraphs 25, 26, 137 and 139]
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Therefore, the teachings of Steinman and Muenz establish that EBV EBNA-1 can elicit a CTL immune response.
Moreover, one of ordinary skill in the art would be motivated to and have a reasonable expectation of success at employing the summarized teachings of Moss et al. and Khanna et al. with the teachings of Steinman and Muenz as evidenced by GenBank Accession YP_401677, to administered a EBV protein that possesses a HLA-A2 epitope, including an epitope that comprises SEQ ID NO: 27 as part of a method to elicit CTL immune responses.
Thus the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was made.
(Prior Rejection Maintained) Claim 32 is rejected under pre-AJA 35 U.S.C. 103(a) as being unpatentable over Steinman and Muenz and GenBank Accession YP_401677 as applied to claims 20-24, 26, 30-31, 33-35 above, and further in view of Bhardwaj et al. (Cancer Journal, 2010, Vol. 16, No. 4, pages 382-391).
The teachings of Steinman and Muenz and YP_401677 are discussed above, however, they do not specifically state that the adjuvant is a TLR4 or TLR9 agonist.
Bhardwaj et al. teach several TLR agonists, such as TLR9 agonists which include CpG [see page 7]. They also teach that TLR agonist adjuvants are import for enhancing immune responses against antigens. [see abstract]
It would have been obvious to one of ordinary skill in the art to modify the composition taught by Steinman and Muenz in order to include an adjuvant, such as a TLR4 or TLR9 adjuvant with their composition. One would have been motivated to do so, given the suggestion by Steinman and Muenz that adjuvants can be included with their composition. There would have been a reasonable expectation of success, given the knowledge that the TLR9 adjuvants, such as CpG, are useful in facilitating immune responses against antigens as taught by Khanna et al. Thus the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Response to arguments:
Applicant presents the following arguments in traversal of the rejection:
Bhardwaj et al. fail to teach the use of a TLR4 and/or TLR9 agonist as an adjuvant with a herpesvirus polypeptide in order to elicit a CD8+ CTL response. Also, nucleic acid based or dendritic cell-based approaches for CTL induction were favored and applicant’s method is a contradiction to the traditional means of inducing CTL responses.
In response, as addressed above, the instant invention does not specify that the immune response is specifically a CD8+ T cell response and as stated above, Steinman and Muenz address this limitation. Furthermore, Steinman and Muenz also teach that protein based administrations have bene successful at eliciting cytotoxic T lymphocyte immune responses and as a result the teachings of Bhardwaj et al. are relevant to one of ordinary skill in the art based on the teachings by Steinman and Muenz to include adjuvants with their EBNA-1 polypeptide. [see paragraph 10]
Thus the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BENJAMIN P BLUMEL whose telephone number is (571)272-4960. The examiner can normally be reached M-F 8-5 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Michael Allen can be reached at (571) 270-3497. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/BENJAMIN P BLUMEL/Primary Examiner, Art Unit 1671