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 .
Application Status
This action is written in response to applicant’s correspondence received 02/12/2024. Claims 1-2, 5-6, 8-13, 15, 17-32, 36-40, 42-44 and 46-50 are currently pending.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Please see p. 39, para [140].Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-2, 5-6, 8-13, 15, 17-32, 36-40, 42-44 and 46-50 are rejected under 35 § U.S.C. 112(b) or 35 § U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The term “substantially free” in claim 1 is a relative term which renders the claim indefinite. The term is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree to which the composition must be free of CTP or ATP, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The dependent claims included in this rejection but not di for failing to remedy the indefiniteness. Applicant is advised to either delete the term “substantially” or amend the claim to recite a specific value or range of values.
Claims 5, 6 and 47 recite the limitation "the composition comprising RNA" in regard to the recited nucleotides. There is insufficient antecedent basis for this limitation in the claims or in claim 1, from which they depend.
Those claims identified in the statement of rejection but not explicitly referenced in the rejection are also rejected for depending from a rejected claim but failing to remedy the indefiniteness therein.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 46 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 46 is drawn to a composition produced by the method of claim 1. A claim to a product is not a proper dependent claim if the product can be made by a method other than that recited in the base method claim, and thus does not include the limitations of the base claim. See MPEP 608.01(n)(III). In the instant case, claim 1 recites a method of producing an RNA which comprise “transcribing” the RNA from a DNA template and “supplementing” the reaction mix. However, RNA molecules may be produced by other methods, such as template-free enzymatic synthesis, as described by Jensen & Davis (Template-Independent Enzymatic Oligonucleotide Synthesis (TiEOS): Its History, Prospects, and Challenges. Biochemistry. 2018 March 27; 57(12): 1821–1832.). For example, see Figure 4, which shows PNPase synthesis of polyribonucleotides.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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:
Determining the scope and contents of the prior art.
Ascertaining the differences between the prior art and the claims at issue.
Resolving the level of ordinary skill in the pertinent art.
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.
Wochner
Claims 1-2, 5-6, 8-13, 15, 17-32, 36-40, 42-44, 46 and 49-50 are rejected under 35 U.S.C. 103 as being unpatentable over WIPO Publication WO 2015/188933 A1 to Wochner (hereinafter ‘Wochner’, applicant’s submission).
Regarding claim 1, Wochner teaches an in vitro method of transcribing RNA from a DNA template using a reaction mix comprising ATP, GTP, CTP and UTP (§Abstract):
The present invention relates to a method for synthesizing an RNA molecule of a given sequence, comprising the step of determining the fraction (1) for each of the four nucleotides G, A, C and U in said RNA molecule, and the step of synthesizing said RNA molecule by in vitro transcription in a sequence-optimized reaction mix, wherein said sequence-optimized reaction mix comprises the four ribonucleoside triphosphates GTP, ATP, CTP and UTP
Wochner teaches wherein the starting concentration of UTP is lower than the starting concentration of CTP and/or ATP in Table 8, showing, e.g., a UTP concentration of 1.8 mM compared to 3.4 mM of GTP, 4.7 mM of CTP, and 3.5 mM of ATP, along with other, similar formulations (p. 53, reproduced below):
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Wocher does not teach supplementing the reaction mix during transcription specifically with a composition that comprises UTP but not ATP or CTP.
However, Wochner does teach fed-batch reactions, in which the reactions are supplemented with 13.45 mM NTPs after 2.5 hours (p. 54 ln 10-11). Wochner also teaches the motivation to do so, i.e., that supplementation of NTPs during transcription reactions (i.e., fed-batch reactions) increases the efficiency of in vitro transcription by maintaining constant reaction conditions over time (p. 5 ln 20-24).
Wochner further teaches that RNA transcribed in vitro by phage polymerases can contain double-stranded RNA contaminants (p. 2 ln 30-31). These contaminants activate the immune response and decrease protein synthesis (p. 3 ln 15). Wochner suggests a solution to the problem, namely reducing UTP concentration, because the formation of dsRNA contaminants seems to be especially sensitive to UTP concentration (p. 3 ln 9-10). Therefore, Wochner provides a teaching, suggestion or motivation to maintain a reduced UTP concentration during the reaction in general, with or without sequence optimization.
It would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have modified Wochner’s method of in vitro transcription using a sequence-optimized reaction mix to further comprise a reaction mix with relatively low initial UTP, and to maintain those low UTP concentrations throughout the reaction by fed-batch supplementation with UTP. Wochner teaches that NTP concentrations and ratios can be optimized for various reasons, including sequence optimization and reduction of dsRNA contaminants. Wochner teaches that reducing UTP can reduce dsRNA contaminants, which would have motivated the ordinary artisan to keep UTP concentrations relatively low. However, based on logic and sound scientific reasoning, a low UTP concentration relative to the other NTPs would, without supplementation, predictably lead to the depletion of UTP before any other NTP is exhausted. Since RNA transcript sequences generally comprise all four nucleotides, premature depletion of UTP would end the reaction before synthesis is complete, which would necessitate UTP supplementation.
Thus in regards to the limitations of the claims, where the prior art teaches methods of optimizing the reaction mix for efficient, low-contaminant in vitro transcription by adjusting the NTP ratios in general, by reducing UTP in particular to reduce dsRNA contamination, and by implementing fed-batch supplementation to maintain those optimized concentrations, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp for optimization of the reaction. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense to provide routine optimization.
Regarding claim 2, insofar as Wochner teaches sequence-optimized reaction mixes and the claims generally encompass any RNA sequence, including those with equal amounts of adenosine and cytosine, Wochner teaches reaction mixes where the starting concentrations of ATP and CTP are equal
Regarding claim 5, Wochner teaches that reducing UTP reduces dsRNA, so that the method of claim 1, performed with relatively low UTP instead of equimolar concentrations of all NTPs, would necessarily achieve the claimed outcome.
Regarding claim 6, since Wochner teaches that reduced UTP concentrations reduce the formation of immunogenic dsRNA, it follows that the reduction of UTP as described in claim 1 and discussed above would necessarily reduce the composition’s immunogenicity.
Regarding claim 8, Wochner teaches wherein the ratio of starting UTP to CTP or ATP is between 1:1.5 and about 1:15 (approximately 1:2 – 1:3, in this case).
Regarding claim 9, it would have been obvious to supplement UTP when it nears depletion to prevent the transcription reaction from ending before completion, as discussed above.
Regarding claim 10, the claims encompass effectively any number of supplementations from one or more. Wochner teaches at least one supplementation, and further, in Example 9 (p. 63-65), that bioreactor conditions can be optimized for repeat feedings to maintain optimal steady state concentrations of the reactants.
Regarding claims 11-12, Figure 18 shows that the bioreactor can be optimized for either a continuous or semi-batch process.
Regarding Claim 13, insofar as Wochner teaches optimizing the relative amounts of NTPs in the reaction mix and maintaining that optimal concentration throughout with fed-batch supplementation, Wochner teaches restoring the original, optimized ratios when feeding.
Regarding claim 15, Wochner further teaches wherein the starting concentration of GTP is lower than ATP or CTP (see Table 8). Wochner teaches that this is done to facilitate capping of the transcribed RNA because the cap directly competes with GTP for incorporation as the start nucleotide, and GTP concentration is typically reduced compared to other NTPs (p. 2 ln 11-16).
Regarding claims 17-25, the same reasoning, mutatis mutandis applies to GTP concentrations and modes of supplementation as applied to UTP above, except that in the case of GTP, the reduced concentration is maintained to facilitate capping rather than reduce dsRNA.
Regarding claim 26, Wochner teaches that a start nucleotide is added to the reaction mix (p. 22 ln 30-32).
Regarding claim 27, Wochner teaches that the start nucleotide is a nucleoside triphosphate (GTP) or monophosphate (GMP) (p. 23 ln 5-6).
Regarding claims 28 and 29, Wochner teaches that the start nucleotide is a cap or cap analog (p. 23 ln 8-9), which is selected from the group consisting of G[5']ppp[5']G, m7G[5']ppp[5']G, m32,2,7G[5']ppp[5']G, m27,3’-OG[5']ppp[5']G (3'ARCA), m27,2’-OGpppG (2'-ARCA), m27,2’-OGppspG D1 (β-S-ARCA D1) and m27,2’-OGppspG D2 (β-S-ARCA D2) (p. 23 ln 11-14).
Regarding claims 30-32, Wochner teaches that the 5’ cap is in excess compared to GTP at a 4:1 ratio (p. 29 ln 6-7).
Regarding claim 36, Wochner teaches that UTP in the reaction mixture was replaced by pseudo-UTP (Figure 8, p. 44 ln 19-20).
Regarding claim 37, Wochner teaches that the functional analog of GTP Is 7-Deaza-GTP (7-deazaguanosine-5'-triphosphate, p. 15 ln 9-10), N1-Methyl-GTP (N1-methylguanosine-5'-triphosphate, p 15 ln 11-12), or O6-Methyl-GTP (O6-methylguanosine-5'-triphosphate, p. 15 ln 13-14).
Regarding claims 38-39, Wochner teaches wherein the DNA template (Example 11, p. 66) and RNA (p. 11 ln 8-10) both comprise a 5’ UTR, 3’ UTR, open reading frame and poly(A)-tail.
Regarding claim 40, Wochner teaches that the RNA encodes at least one peptide or protein (Table 1, p. 49).
Regarding claims 42-44, Wochner teaches performing the method in a bioreactor, which keeps the pH of the reaction mix constant and monitors the transcription in real time:
Furthermore, other critical process parameters, such as a pH-value of the filtrated fluid, or a conductivity of the filtrated fluid can be analyzed by further suitable sensors of the sensor unit 41. Data collection and analyses by the controller 42, usually in the form of a computer based system or the like, allows the control of the feed pump 43 as an actuator for repeated feeds of nucleotides, buffer components and/or enzymes into the reaction module 2, as well as the control of further pumps in the bioreactor 1 in order to adjust key process parameters in optimal steady-state reaction conditions. (p. 64 ln 19-25)
The application of a sequence optimized ribonucleotide mix in the bioreactor 1 enables a real-time measurement of the nucleotide concentration in the filtration compartment 23 during the RNA transcription reaction in the reaction core 22 of reaction module 2. (p. 64 ln 12-15)
Regarding claim 46, Wochner teaches compositions produced by the method of claim 1, as discussed above.
Regarding claims 49-50, Wochner teaches a method of in vitro transcription of RNA comprising restricting concentration of UTP, and further teaches an RNA template comprising a promoter
Wochner and Van Hoecke
Claims 47 and 48 are rejected under 35 U.S.C. 103 as being unpatentable over Wochner, as applied to claims 1-2, 5-6, 8-13, 15, 17-32, 36-40, 42-44, 46 and 49-50, further in view of Van Hoecke (Van Hoecke et al. Treatment with mRNA coding for the necroptosis mediator MLKL induces antitumor immunity directed against neo-epitopes. Nat Commun. 2018 Aug 24;9:3417.)
Claim interpretation: The instant specification does not provide an explicit definition of “treating”. In the absence of an explicit definition, the broadest reasonable interpretation encompasses administration, to any subject, for various purposes, any RNA molecule of any kind, including mRNA, miRNA, rRNA, tRNA, ribozymes, etc., of any length, with any nucleobase sequence or secondary structure, and all of the functions which derives from those structures.
Wochner renders obvious the method of claims 1 and 46, from which instantly rejected claims depend, as described above.
Wochner does not teach a method of administering the RNA.
However, Wochner does suggest that therapeutic RNA molecules represent an emerging class of drugs (p. 1 ln 9) and provides a method of producing less immunogenic (Fig. 23, p. 74 ln 16-19) mRNA with higher yield (p. 72 ln 7-11) and protein expression (p. 74 ln 1-4) compared to standard methods.
Van Hoecke teaches, “an antitumor therapy that is based on the intratumor delivery of mRNA that codes for the necroptosis executioner mixed lineage kinase domain-like (MLKL) protein” (§Abstract). Van Hoecke also teaches that the mRNAs were “hypo-inflammatory” (p. 2) and “strongly suppressed tumor growth” in mice “inoculated with lymphoma-derived cancer cells” (p. 11). While Van Hoecke does not teach that the mRNA was purified using the instantly claimed method, they do note that the mRNA was in vitro transcribed and purified (p. 14).
It would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have combined the teachings of Wochner and Van Hoecke by using Wochner’s method to synthesize MLKL mRNA for anti-tumor therapy. Van Hoecke indicates that their purified mRNA was effective at suppressing tumor growth, while Wochner indicates that their method yields mRNA with high yields, high expression, and low immunogenicity. The skilled artisan would have had a reasonable expectation of success based on the combination of Wochner’s teachings regarding the effectiveness of their method and Van Hoecke’s teaching regarding the therapeutic efficacy of expressing KLKL to suppress the growth of lymphoma.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-2, 5-6, 8, 15 and 17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 102, 104, 107, 108, 116-117 and 119 of copending Application No. 19/176,998 in view of Wochner. Although the claims at issue are not identical, they are not patentably distinct from each other because the copending claims recite a method of producing a RNA molecule through in vitro transcription wherein a reaction mixture is created comprising a lower concentration of UTP relative to CTP (instant claims 1, 8 and copending claim 102) and UTP/GTP relative to ATP (instant claims 15, 17 and copending claim 107). Copending claim 104 recites a range of molar ratios for CTP to UTP comprising 1.5 (1:1.5) to 1.8 (1:1.8), which lies within the instantly claimed range (instant claim 8). Copending claim 107 recites a molar ratio of 1.50, which falls within the instantly claimed range. Copending claims 116-117 recite reduced amounts of dsRNA, as required by the limitations of instant claims 5 and 6. Copending claim 119 recites wherein the RNA is a therapeutic RNA, which is a species of RNA encompassed by instant claim 1.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 1-2, 5-6, 8, 15 and 17 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-4, 6-7, 15-16 and 18 of U.S. Patent No. 12,305,210. Although the claims at issue are not identical, they are not patentably distinct from each other because the patented claims recite a method of producing an RNA molecule via in vitro transcription which recites the same relative amounts and molar ratios of UTP/GTP to ATP/CTP (patented claims 1, 3-4, 6-7, instant claims 1-2, 8, 15, 17), the same reduction in dsRNA as an outcome of the method (patented claims 15-16, instant claims 5-6), and the same therapeutic RNA molecule (patented claim 18, instant claim 1) discussed above for copending Application 19/176,998.
Conclusion
No claims are allowed at this time.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMANDA M ZAHORIK whose telephone number is (703)756-1433. The examiner can normally be reached M-F 8:00-16:00 EST.
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/A.M.Z./Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636