Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
DETAILED ACTION
Claims 28, 30-33, 37-40, 44, 46, and 48-51 are pending.
Claim 28 is currently amended.
Claims 38-40, 48, and 49 are withdrawn.
Claims 28, 30-33, 37, 44, 46, 50, and 51 are under examination on the merits.
Rejections Maintained
35 U.S.C. 103
The rejection of claims 28, 30, 37, 44, 46, 50, and 51 under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Hadden et al. (WO 2010/132867, international publication date: 11/18/2010, IDS) in view of Akiyama et al. (Anticancer Research, 24: 571-578, 2004), Mockey et al. (Cancer Gene Therapy, 14: 802-814, 2007), and Fotin-Mleczek et al. (WO 2009/030481, international publication date: 03/12/2009) is maintained.
The rejection of claims 31 and 32 under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Hadden et al. (WO 2010/132867, international publication date: 11/18/2010, IDS) in view of Akiyama et al. (Anticancer Research, 24: 571-578, 2004), Mockey et al. (Cancer Gene Therapy, 14: 802-814, 2007), and Fotin-Mleczek et al. (WO 2009/030481, international publication date: 03/12/2009), as applied to claims 28, 30, 37, 44, and 46, and further in view of Barner et al. (WO 2009/046974, international publication date: 04/16/2009, IDS) is maintained.
Nonstatutory Double Patenting
The provisional rejection of claims 28, 30, 37, 44, 46, 50, and 51 on the ground of nonstatutory double patenting as being unpatentable over claims 18, 24, 33, 35, and 36 of copending Application No. 16/848,991 in view of Hadden et al. (WO 2010/132867, international publication date: 11/18/2010, IDS), Akiyama et al. (Anticancer Research, 24: 571-578, 2004), and Fotin-Mleczek et al. (WO 2009/030481, international publication date: 03/12/2009) is maintained.
The provisional rejection of claims 31 and 32 on the ground of nonstatutory double patenting as being unpatentable over claims 18, 24, 33, 35, and 36 of copending Application No. 16/848,991 in view of Hadden et al. (WO 2010/132867, international publication date: 11/18/2010, IDS), Akiyama et al. (Anticancer Research, 24: 571-578, 2004), and Fotin-Mleczek et al. (WO 2009/030481, international publication date: 03/12/2009), as applied to claims 28, 30, 37, 44, and 46, and further in view of Barner et al. (WO 2009/046974, international publication date: 04/16/2009, IDS) is maintained.
The rejection of claims 28, 30, 37, 44, 46, 50, and 51 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 5, 12,14, 18, and 19 of U.S. Patent No. 9,234,013 in view of Hadden et al. (WO 2010/132867, international publication date: 11/18/2010, IDS) and Akiyama et al. (Anticancer Research, 24: 571-578, 2004) is maintained.
The rejection of claims 31 and 32 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4,5, 12, 14, 18, and 19 of U.S. Patent No. 9,234,013 in view of Hadden et al. (WO 2010/132867, international publication date: 11/18/2010, IDS) and Akiyama et al. (Anticancer Research, 24: 571-578, 2004), as applied to claims 28-30, 34, 35, 37, and 41, and further in view of Barner et al. (WO 2009/046974, international publication date: 04/16/2009, IDS) is maintained.
The rejection of claims 28, 30, 33, 37, 44, 46, 50, and 51 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 5, 4, 9, and 12-15 of U.S. Patent No. 10,010,592 in view of Hadden et al. (WO 2010/132867, international publication date: 11/18/2010, IDS) and Akiyama et al. (Anticancer Research, 24: 571-578, 2004) is maintained.
The rejection of claims 31 and 32 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2,5, 4,9, and 12-15 of U.S. Patent No. 10,010,592 in view of Hadden et al. (WO 2010/132867, international publication date: 11/18/2010, IDS) and Akiyama et al. (Anticancer Research, 24: 57 1-578, 2004), as applied to claims 28-30, 34, 35, 37, and 41, and further in view of Barner et al. (WO 2009/046974, international publication date: 04/16/2009, IDS) is maintained.
The rejection of claims 28, 30, 33, 37, 44, 46, 50, and 51 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 4, 5, 9, and 12-16 of U.S. Patent No. 11,110,156 in view of Hadden et al. (WO 2010/132867, international publication date: 11/18/2010, IDS) and Akiyama et al. (Anticancer Research, 24: 571-578, 2004) is maintained.
The rejection of claims 31 and 32 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 4, 5, 9, and 12-16 of U.S. Patent No. 11,110,156 in view of Hadden et al. (WO 2010/132867, international publication date: 11/18/2010, IDS) and Akiyama et al. (Anticancer Research, 24: 571-578, 2004), as applied to claims 28-30, 34, 35, 37, and 41, and further in view of Barner et al. (WO 2009/046974, international publication date: 04/16/2009, IDS) is maintained.
Response to Arguments
In Applicant Arguments, dated 02/06/2026, Applicant asserts that the Office has improperly relied on the combination of Hadden et al. and Akiyama et al. to reject the claims under 35 U.S.C. 103. Specifically Applicant asserts that “Hadden is fundamentally directed to cytokine-based immunotherapy, centered on administration of a leukocyte-derived biologic (e.g., IRX-2) to enhance immune responses, and any reference to tumor antigens in Hadden is ancillary to, and dependent upon, the presence of cytokine adjuvants. In contrast, the pending claims are directed to cytokine-free compositions comprising substantially purified RNA molecules formulated with cationic lipids, wherein immune stimulation is achieved through in vivo expression of encoded tumor antigens rather than through exogenous immune modulation. The Examiner's position requires removal of the central feature of Hadden, cytokine-mediated immune enhancement, without any teaching or suggestion in Hadden that antigen expression alone, let alone RNA-based antigen expression, would be sufficient to elicit a therapeutic immune response.”
These arguments have been fully considered but are not deemed persuasive. Hadden et al. teach “the present invention is directed to a composition including synergistic amounts of a primary cell-derived biologic (IRX-2) having the cytokines IL-1, IL-2, IL-6, IL-8, TNF-α, and IFN-γ, and a cancer vaccine including at least one antigen. IRX-2 acts as an adjuvant alone or in combination with other adjuvants to the exogenous antigen(s) in the vaccine, i.e. it stimulates an immune response to the exogenous antigen. In other words, IRX-2 acts in a synergistic manner with the exogenous antigen to create a greater immune response than can be achieved by administering the exogenous antigens alone. IRX-2 provides advantages over previous adjuvants because of its affect of completely ‘turning on’ the immune system of a patient whose immune system is in any way suppressed from its full function.” See [00098]. At [000102], Hadden et al. teach that common antigens used in cancer vaccines include NY-ESO1, tyrosinase, and MAGE proteins. At [000104], Hadden et al. teach that “the antigens can be encoded in a viral or bacterial vector, i.e. a nucleic acid vector. In this case, the antigen is encoded in nucleic acid material, such as DNA or RNA (emphasis added).” Therefore Hadden et al. teach that RNA-encoded antigens, such as NY-ESO1, tyrosinase, and MAGE, may be used in the preparation of cancer vaccines. Hadden et al. further teach that said antigens may be administered with the adjuvant IRX-2, which comprises the cytokines IL-1, IL-2, IL-6, IL-8, TNF-α, and IFN-γ. Even if Hadden et al. did not teach the adjuvant IRX-2, the reference still provides motivation to prepare cancer vaccines that comprise RNA-encoded antigens, such as NY-ESO1, tyrosinase, and MAGE. Furthermore Applicant’s assertion that “the pending claims are directed to cytokine-free compositions comprising substantially purified RNA molecules” is not persuasive, because the claims recite an immune-stimulating composition comprising RNA-encoded antigens, such as NY-ESO1, tyrosinase, and MAGE, and only one of the claims (dependent claim 51) requires a composition that is cytokine-free.
Applicant further asserts that “Akiyama is directed exclusively to a fundamentally different vaccination paradigm, namely ex vivo dendritic cell-based peptide vaccines. Akiyama relies on short, HLA-restricted synthetic peptide epitopes that are pulsed onto dendritic cells outside the body, followed by reinfusion of antigen-loaded immune cells to induce cytotoxic T lymphocytes. This DC vaccine regime is mechanistically and operationally distinct from the presently claimed mRNA vaccine compositions… Although Akiyama discusses categories of melanoma-associated antigens in a general scientific context, its actual experimental disclosure is limited to specific peptide epitopes and expressly excludes NY-ESO from the tested peptide cocktail…”
These arguments have been fully considered but are not deemed persuasive. One of ordinary skill in the art would have been motivated to prepare cancer vaccines that comprise one or more of the six melanoma-associated antigens described by Akiyama et al., because there would have been a reasonable expectation that a cancer vaccine comprising one or more of the six melanoma-associated antigens described by Akiyama et al. (which includes tyrosinase and MAGE-A3) and IRX-2 would elicit immune responses against melanoma, thereby providing a therapeutic benefit to melanoma patients. As such even though 1) Akiyama et al. is primarily directed to dendritic cell-based cancer vaccines and 2) Akiyama et al. do not specifically blend the NY-ESO antigen into a cancer vaccine, in view of the teachings of the cited references, one of ordinary skill in the art would have had ample motivation to prepare a cancer vaccine that comprises RNA-encoded antigens, such as NY-ESO; MAGE proteins; and tyrosinase. The claimed vaccination platform is taught by Hadden et al., and in light of the teachings of Akiyama et al., there would have been a reasonable expectation that modifying the vaccination platform of Hadden et al. to comprise a MAGE-A3 antigen would result in an invention that is of therapeutic value in treating melanoma.
Applicant further asserts that “the Examiner’s combination improperly conflates disparate technologies by treating DC-based peptide vaccines, cytokine adjuvant therapies, and mRNA vaccines as interchangeable components. A person of ordinary skill in the art would have recognized that DC vaccines and mRNA vaccines present distinct technical challenges, operate through different biological mechanisms, and were pursued as separate and alternative strategies in the field. The cited references provide no rationale for abandoning the ex vivo DC pulsing required by Akiyama, eliminating the cytokine adjuvants central to Hadden, and instead adopting a lipid-formulated, substantially purified RNA vaccine relying on in vivo antigen expression.”
These arguments have been fully considered but are not deemed persuasive. One of ordinary skill in the art would appreciate that DC-based peptide vaccines, cytokine adjuvant therapies, and mRNA vaccines are different technologies; however these technologies are based upon the scientific principle that tumor antigens may be used to elicit anti-tumor immune responses. Based upon the teachings of Hadden et al. and Akiyama et al., one of ordinary skill in the art would reason that NY-ESO1, tyrosinase, and MAGE-A3 are tumor antigens in melanoma, and one of ordinary skill in the art would have thus had ample motivation to blend these tumor antigens into a DC- or mRNA-based vaccine platform for the treatment of melanoma.
Applicant further asserts that “the rejection fails to account for the substantial structural and compositional limitations recited in the pending claims, limitations that are not taught or suggested by the asserted combination. The claims require substantially purified RNAs that include a defined 5' cap, a heterologous 3' untranslated region, and a poly(A) tail within a specified range, and further require that the RNAs are in complex with a cationic lipid. The Examiner's rationale depends on assembling these features from separate references without any articulated reason why a person of ordinary skill in the art would have combined such features in the particular claimed manner to solve the problem addressed by Applicant. The Office Action itself acknowledges that Mockey is relied upon for poly(A) tail length and cationic lipid transfection generally, and that Fotin-Mleczek is relied upon for generic RNA stabilization via 3' UTRs. However, neither reference provides guidance or motivation toward the claimed multivalent, lipid-complexed RNA composition encoding a specific combination of tumor antigens.”
These arguments have been fully considered but are not deemed persuasive. As indicated at p. 16-18 of the Final Rejection, dated 01/21/2025, one of ordinary skill in the art would have been motivated with a reasonable expectation of success at the effective filing date of the invention to combine the teachings of Hadden et al., Akiyama et al., Mockey et al., and Fotin-Mleczek et al. to develop an immune-stimulating composition comprising: i) a RNA comprising a coding region encoding NY-ESO1 tumor antigen; ii) a RNA comprising a coding region encoding MAGE-A3 tumor antigen; and iii) a RNA comprising a coding region encoding Tyrosinase tumor antigen, wherein said RNAs are substantially purified and wherein each of said RNAs comprises, from 5' to 3', a methylated 5' cap, a 5' untranslated region (UTR), the coding region, a heterologous 3' UTR, and a poly(A) sequence of about 60 to about 250 adenosine nucleotides and wherein said RNAs are in complex with a cationic lipid. One of ordinary skill in the art would have been motivated to do so, because Hadden et al. teach or suggest an immune-stimulating composition comprising: i) an RNA comprising a coding region encoding NY-ESO1 tumor antigen; ii) an RNA comprising a coding region encoding MAGE-A3 tumor antigen; and iii) an RNA comprising a coding region encoding tyrosinase tumor antigen. Furthermore in view of the teachings of Akiyama et al., one of ordinary skill in the art would have been motivated to modify the teachings of Hadden et al. to develop a polyvalent immunotherapy composition using multiple epitopes from melanoma antigens, such as NY-ESO, MAGE-A3, and tyrosinase, because there would have been a reasonable expectation that said polyvalent immunotherapy composition would be effective in the treatment of melanoma. Additionally based upon the teachings of Mockey et al., one of ordinary skill in the art would have been motivated at the effective filing date of the invention to prepare mRNA cancer vaccines to comprise melanoma-associated antigen mRNA carrying a 100 adenosine-long poly(A) tail, wherein said mRNA cancer vaccines are complexed with cationic lipids, because Mockey et al. teach that cationic lipids are efficient vectors in transfecting various cell types. Also Fotin-Mleczek et al. teach that mRNA sequences may be stabilized using the 3’UTR of the alpha globin gene, which meets the limitation of a heterologous 3’ UTR. At p. 71, Fotin-Mleczek et al. teach that the 5’ cap structure may be m7G(5’)ppp, which is a methylated 5’ cap. At p. 23, Fotin-Mleczek et al. teach that RNAs of the invention may comprise a 5’ UTR. By combining the teachings of Hadden et al., Akiyama et al., Mockey et al., and Fotin-Mleczek et al., one of ordinary skill in the art would arrive at an immune-stimulating composition comprising: i) a RNA comprising a coding region encoding NY-ESO1 tumor antigen; ii) a RNA comprising a coding region encoding MAGE-A3 tumor antigen; and iii) a RNA comprising a coding region encoding Tyrosinase tumor antigen, wherein each of said RNAs comprises, from 5' to 3', a methylated 5' cap, a 5' UTR, the coding region, a heterologous 3' UTR, and a poly(A) sequence of about 60 to about 250 adenosine nucleotides and wherein said RNAs are in complex with a cationic lipid. One of ordinary skill in the art would have been motivated to prepare such an immune-stimulating composition, because there would have been a reasonable expectation the said immune-stimulating composition is effective in treating melanoma. Furthermore it would have been prima facie obvious at the time of the invention to prepare cancer vaccines that comprise purified RNA molecules that are free from contaminants, such as excess nucleotides and template DNA. For example at p. 90, Fotin-Mleczek et al. teach that various methods, such as chromatography and gel filtration, may be used to purify RNA from contaminants, such as excess nucleotides and template DNA.
Applicant also asserts that “the Examiner's treatment of claim 51, which affirmatively requires that the composition is ‘substantially free of cytokines,’ is legally and factually deficient. The Office Action reasons that, because Hadden generally discusses historical non-cytokine adjuvants such as alum or saponins, a person of ordinary skill in the art would have been motivated to prepare a cytokine-free vaccine. However, claim 51 does not merely permit the use of a non-cytokine adjuvant, nor does it recite a vaccine ‘with’ an alternative adjuvant; rather, claim 51 expressly excludes cytokines from the composition. The Examiner's rationale improperly assumes the addition of other adjuvants while failing to explain why a skilled artisan would remove IRX-2, the central immune-stimulating component of Hadden.”
These arguments have been fully considered but are not deemed persuasive. Page 9 of the Non-Final Rejection, dated 08/06/2025, states that although Hadden et al. is primarily concerned with cytokine adjuvants, Hadden et al. teach that there are other adjuvants that improve immune responses. For example at [00013], Hadden et al. teach that “[f]ailure to evoke a sufficient immune response with traditional vaccines has remained a challenge for vaccine development. Adjuvants have thus been developed to accelerate, enhance, and prolong the immune response to vaccination and reduce the amount of antigen needed per dose. Adjuvants have been used for almost 100 years. Le Moignic and Pinoy first recognized that Salmonella typhimurium suspended in mineral oil potentiated immune responses in 1916. In 1926, Ramon demonstrated that an antitoxin response could be augmented by a large range of substances such as agar, tapioca, lethicin, starch oil, saponin, and breadcrumbs, and Glenny used aluminum salt to precipitate diphtheria toxoid improving immunogenicity, leading to alums used today. Quil A was determined to have adjuvant properties in 1936 by Thibaud and Richou. Quil A is a triterpenoid saponin extracted from the bark of the South American Molina soap tree Quillaja saponaria. In 1937, Freund also developed adjuvants from emulsions. Little progress has been made since then. As we begin to understand the immune system as described above, more progress is being made with adjuvants. Several adjuvants have been developed for vaccines, including cancer vaccines, but still only alum has really had success worldwide. Alum is a Th2 adjuvant; however, adjuvants providing a Th1 response are also desired. Adjuvants are especially needed for population groups that do not sufficiently respond to conventional vaccines due to impaired immune response, such as elderly or immunosuppressed patients.” Based upon these teachings, one of ordinary skill in the art would reason that non-cytokine adjuvants, such as alum, are capable of improving the immune response to vaccination. One of ordinary skill in the art would have had ample motivation to prepare cancer vaccines with a non-cytokine adjuvant, such as alum, because the resultant cancer vaccines would reasonably be expected to treat cancer. As such the teachings of Hadden et al. provide ample motivation to prepare cancer vaccines that are substantially free of cytokines. The rejection of the claims under 35 U.S.C. 103 have been deemed proper and are maintained. By the same reasoning the nonstatutory double patenting rejections of record have also been maintained.
Conclusion
No claims are allowed.
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 extension fee 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 NELSON B MOSELEY II whose telephone number is (571)272-6221. The examiner can normally be reached on M-F 9:00 am - 6:00 pm EST
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/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642
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