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 .
Election/Restrictions
Applicant’s election without traverse of Group I (i.e., claims 1-4, 6-8, 11, and 62 drawn to a method of inhibiting p450-mediated toxicity) in the reply filed on Sep 19, 2025, is acknowledged. Additionally, Applicant’s election without traverse of the following Species:
One or more miR-375 molecules, in the reply filed on July 12, 2024, is acknowledged.
In light of the dependence of claim 62 on non-elected claim 60, which in turn depends from claim 50, Examiner has extended the elected Group to include claims 50 and 60 from unelected Group. However, the newly included claims will only be examined for the elected species of original Group I.
Claims 19-20, 27-28, 5 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Groups, there being no allowable generic or linking claim. Election was made without traverse (no argument was made) in the reply filed on Sep 19, 2025.
Status of Claims
Claims 1-4, 6-8, 11, 50, 60, and 62 are under consideration.
Drawings
The drawings are objected to as failing to comply with 37 CFR 1.84(u)(1) because:
the view numbers for the partial views for Figure 5 that appear on several sheets are followed by "Continued" instead of the same number followed by a capital letter such as FIG. 5A, FIG. 5B, etc.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because of the following informalities:
Pg. 2, lines 9 – 11 disclose: In some embodiments, a miR-375 molecule comprises a sequence that is at least 70%< 80%, 90%, 99% or more identical to the nucleic acid sequence set forth in SEQ ID NO: 1.
The terms in bold do not make sense. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claim 60 is 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.
Claim 60 recites the limitation "the rAAV vector of claim 50" in line (i). There is insufficient antecedent basis for this limitation in the claim. Claim 50 recites an isolated nucleic acid but makes no mention of an rAAV vector.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Claims 1-4, 6-8, 11, 50, 60, and 62 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Scope of the Invention
The rejection is limited to the elected invention (i.e., elected Group I wherein claim 1 is directed to a method for inhibiting CYP450-mediated toxicity comprising administering to the cell an isolated nucleic acid encoding one or more miR-375 molecules). No limiting definition for CYP450-mediated toxicity is provided.
The broadest reasonable interpretation of the claimed method is:
Treating all forms of CYP450-mediated toxicity by administration of an isolated nucleic acid molecule of any length (i.e., thousands of nucleotides) comprising at least one miRNA, wherein each of the miRNAs are operably linked in any configuration to the rest of the nucleic acid (claims 1 and 50).
The isolated nucleic acid molecule and the end-goal disclosed above are each a broad genus. The end-goal of the method is to inhibit p450-mediated toxicity (claim 1 preamble).
Disclosure of a Complete or Partial structure
i) CYP450-mediated toxicity:
A mouse model of (APAP)-induced liver damage is described. The mouse is administered an AAV encoding one miR-375 molecule. The figures disclose results of such administration. Figures 1 – 2 disclose improved liver ALT levels and H&E-stained liver sections in the mouse model. Figure 3 discloses improved hepatic GSH and APAP metabolism. Figures 4 – 6 disclose quantified transcriptomic changes. Figures 7 – 8 disclose observed H&E-stained liver sections in a mouse following APAP dosing.
ii) isolated nucleic acids encoding miR-375:
Pg. 45, Example 2 provides an example of hepatocyte-specific overexpression of certain miRNAs. This includes an rAAV encoding a single miR-375 transgene under the control of a thyroxine binding globulin (TBG) promoter. In pg. 3 lines 4 – 6, the specification discloses: In some embodiments, a miR-375 molecule comprises the sequence set forth in SEQ ID NO: 1 or is
encoded by the sequence set forth in SEQ ID NO: 2. The sequences are fully disclosed. SEQ ID NO: 2, when transcribed, results in one miR-375 molecule.
Species not Disclosed
Applicants claim is broader than what is described in the corresponding disclosure.
i) Claim 1 encompasses a broad category of toxicity, namely CYP450-mediated toxicity. In Pg. 8 CYP450-mediated toxicity is described as manifesting in many different ways. Some examples are: the hepatic CYPs mediate liver toxicity by activating drugs (e.g., APAP) to toxic metabolites. In some embodiments, binding of toxic metabolites of drugs to CYP leads to the formation of anti-CYP antibodies and immune mediated hepatotoxicity. Treatment may involve reducing CYP expression level and/or activity.
ii) Claims 1 and 50 encompass an isolated nucleic acid molecule consisting of more than one miR-375 (SEQ ID NO: 1). The specification discloses that in some embodiments, a miR-375 molecule comprises a sequence that is at least 70% … or more identical to the nucleic acid sequence set forth in SEQ ID NO: 1 (Pg. 2, lines 9 – 11).
However, the disclosure does not provide written support for the types of structures that are required for treating the whole genus of CYP450-mediated toxicity with the isolated nucleic acid molecule as recited.
Although the specification discloses: ALT and GST and gross and microscopic liver changes, the specification does not disclose any CYP450 enzyme per se. Similarly, isolated nucleic acids and rAAV vectors encoding miR-375 molecules could have various structures, e.g., dsRNA, siRNA, shRNA, miRNA, amiRNA, ASOs, DNA or RNA aptamers, etc., (Pg. 1, lines 19 – 21) the specification does not describe any of these structures that comprise even two miR-375, let alone any more. Each of the various disclosed structures of isolated nucleic acids and vectors is in itself a genus of isolated nucleic acid molecules which require its own method of preparation and followed by testing to adequately meet the functional requirement. Further, the genus of more than one miR-375 as recited, will include substantially different structures. The sole species of one miR-375 disclosed in the specification cannot represent the substantial structural variations that are encompassed in the genus of isolated nucleic acid molecules that comprise more than one miR-375 molecules. Since it is unpredictable that a structure synthesized would act as intended in vitro, it would be unpredictable in vivo. Claim 3 requires that the isolated nucleic acid molecule be administered to a human subject.
Given the breadth of structures embraced in the instantly claimed genus, one could not envision the member species comprised in this genus.
Regarding the end-goal: The specification provides no information on: i) CYP450-mediated toxicity with ii) any isolated nucleic acid molecule comprising miR-375 except for i) APAP-induced liver damage with ii) a rAAV vector comprising one pre-miR-375. Further, the scope of the claimed invention is broad and the skilled artisan would not be able to envisage the entire genus claimed of structures that inhibit CYP450-mediated toxicity.
Knowledge from the Art
I. Abdelmonem (Biomedicines. 2024 Jul 2;12(7):1467. ) teach biotransformation of drugs (xenobiotics) into inactive or active forms by Phase I and Phase II enzymes often leads to toxicity (introduction). The CYP450 family of enzymes make up the Phase I enzymes. The CYP450 family of enzymes vary with each subfamily being specific for certain types of drugs (Table 1). The enzymes further vary based on polymorphisms and mutations (pgs. 2 – 7). Upstream of the CYP450 genes, in the biotransformation pathway, are various nuclear receptors. Xenobiotic binding to nuclear receptors turns on expression of CYP450 genes, which in turn will activate the Phase I and II detoxification system (Fig. 1). AhRs, a ligand-activated transcriptional factor that binds to the Aryl hydrocarbon receptor nuclear translocator (ARNT), initiates the expression of downstream CYP450 family of genes (§6.1). However, as discussed earlier in this para, the polymorphisms and mutations in CYP enzymes make elucidating a robust predictive model for drug metabolism and CYP450-mediated toxicity difficult.
II. Qiu (Qiu et al., Biochem Biophys Res Commun. 2011 Jun 24;411(2):276–280.) Qiu evidences the state of the art, around the time of filing of instant application, with respect to creating expression vectors to express more than one copy of miRNA. Qiu evidences multiple miRNAs can be co-transcribed (from a single vector). However, the effect that is hoped to be achieved by expressing more than one copy of miRNA also depends upon available binding sites on target mRNAs. See recitation from para 4 on pg. 2:
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Qiu further evidences the following may be hindrances to incorporating multiple miRNAs in one nucleic acid molecule (pg. 5, 3rd para; pg. 6, 2nd para; pg. 4, 2nd para):
1. length of the primary transcript; therefore increasing the number of encoded miRNAs may reduce transcription efficiency.
2. inserts of ~120 bp surrounding the pre-miRNAs have been demonstrated to be processed into multiple miRNA transcripts; However, instant SEQ Id NO: 2 that encodes miR375 is 283bp long.
3. knowledge of both the hairpin structure and the junction between the single- and double-region of the pri-miRNA (SD junction); no such sequence has been disclosed in the case of instant miRNA.
Thus, the art evidences significant support for CYP450 enzymes as responsible for drug-induced toxicity but makes clear that reliance on upregulation of one enzyme to predict such toxicity is insufficient. Also, the art evidences that multiple miRNAs may be incorporated into a single nucleic acid molecule albeit after a number of parameters have been met.
Structure/Function Correlation
The art evidences that nucleic acid molecules encoding more than one miRNA must have a specific structure in order to perform the role of transcribing more than one miRNA efficiently. There is no essential structure of record required for nucleic acid molecules comprising more than one miRNA that would support the written description for the genus of nucleic acid molecules that are encompassed within the scope of the invention. The skilled artisan cannot envision for e.g., a 2-mer of miRNAs, based on the nucleic acid molecules described in the specification. Other than generically contemplating these molecules, the specification does not provide adequate written description of the nucleic acid molecule of more than one miRNA. See MPEP 2163, Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017). While it is acknowledged that it is routine and conventional to prepare these molecules, in view of MPEP 2163, adequate written description of nucleic acid molecules comprising more than one miRNA requires more than just generically contemplating the species of inhibitors. In view of the lack of description for these species, the skilled artisan would have to empirically determine if they have the desired biological activity.
Conclusion
The written description requirement for the claimed genus of nucleic acid molecules is not satisfied through sufficient description of a representative number of species. There is substantial variation within the genus of: CYP450-mediated toxicity and nucleic acid molecules comprising more than one miRNA, and the applicant does not describe a sufficient variety of species to reflect the variation within the genus. See Enzo Biochem., 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004)(“[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.”). See also MPEP §2163. Applicant has not provided a nexus between the structure of the claimed nucleic acid molecules and the claimed function of transcribing more than one miRNA, and therefore one of ordinary skill would not be able to envision the requisite structural elements from the instant disclosure at the time of filing.
In view of the foregoing, it is clear that the instant specification fails to convey that the inventors had possession of the genus of methods for inhibiting cytochrome p450-mediated toxicity in a cell and the genus of nucleic acid molecules in claim 1, as of the effective filing date sought in the instant case. Only inhibition of AhR-mediated toxicity with a single miRNA, and not the full breadth of the claims, is supported by Applicant’s disclosure.
Dependent claims 2-4, 6-8, 11, are also rejected because they depend on Claim 1, and dependent claims 60 and 62 are also rejected because they depend on Claim 50, and do not remedy the issues of lack of written description as discussed above.
Examiner Suggestion: Limit the claims to APAP or AhR-induced toxicity with miR-375 encoding vector, as there is adequate written description support in the disclosure and prior art for these limitations.
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-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) 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 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 –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1 is rejected under 35 U.S.C. 102a(1) as being anticipated by Papageorgiou (Papageorgiou I. et al., Biochem Pharmacol. 2016 Aug 13;117:78–87.) as evidenced by Abdelmonem (Biomedicines. 2024 Jul 2;12(7):1467. ) (Claim 1).
Regarding claim 1, Papageorgiou teaches a method for inhibiting repression of endogenous AhR (aryl hydrocarbon receptor) protein (by 40%) and mRNA (by 10%), as well as enzyme activity and/or mRNA of AhR regulated enzymes including UGT1A1, UGT1A6, and CYP1A2 (abstract). The method comprises administering miR-375 to cells (HEK293T cells were co-transfected pre-miR for miR-375 LS180 cells were transfected with mature miRNA mimics (miR-375), Methods sections 2.5 and 2.6, pg. 80-81). The results show that hepatic AhR mRNA expression is inversely correlated with miR-375 expression in human liver, miR-375 overexpression downregulates the AhR target genes UGT1A1, UGT1A6, and CYP1A2, but not UGT2B7 in LS180 cells (Figure 5. -Figure 6, section 3.4.- 3.6, pgs. 83 -84). See also graphical abstract reproduced below:
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Although Papageorgiou is silent with respect to the preamble in (claim 1) (for inhibiting cytochrome p450-mediated toxicity in a cell), Papageorgiou anticipates all of the claimed steps, so the functional effects of the claimed steps are considered to be inherent in the method taught by Papageorgiou. As evidenced by Abdelmonem, nuclear receptors such as aryl hydrocarbon receptor (AhR) regulate the transcription of CYP450 genes. Thus, Papageorgiou’s method of repressing AhR is a method for inhibiting cytochrome p450-mediated toxicity in a cell.
Where, as here, the claimed and prior art products are identical or substantially identical, or are produced by identical or substantially identical processes, the PTO can require an applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his claimed product. See In re Ludtke 441 F.2d 660, 169 USPQ 563 (CCPA 1971). Whether the rejection is based on "inherency" under 35 USC 102, or "prima facie obviousness" under 35 USC 103, jointly or alternatively, the burden of proof is the same, and its fairness is evidenced by the PTO's inability to manufacture products or to obtain and compare prior art products. In re Best, Bolton, and Shaw, 195 USPQ 430, 433 (CCPA 1977) citing In re Brown, 59 CCPA 1036, 459 F.2d 531, 173 USPQ 685 (1972).
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-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) 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 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1 and 2 are rejected under 35 U.S.C. 103 as being unpatentable over Papageorgiou (Papageorgiou I. et al., Biochem Pharmacol. 2016 Aug 13;117:78–87; ISR) as evidenced by Abdelmonem (Biomedicines. 2024 Jul 2;12(7):1467. ) (Claim 1) as applied to claim 1 above, and further in view of Shalek (US 20230053540 A1, IDS).
Regarding claim 1, the teachings of Papageorgiou have been discussed above for claim 1 under §102 and are similarly applied.
Regarding claim 2, Papageorgiou teaches acetaminophen undergoes oxidation by cytochrome P450 (CYP) enzymes to a hepatotoxic reactive metabolite (pg. 78, right col.).
Papageorgiou does not administer APAP to a cell or subject to result in an APAP overdose.
However, before the effective filing date of instant application, Shalek teach methods of treating liver injury in a mouse model where Shalek first administer APAP to a mouse and monitor and treat the resulting APAP toxicity (title, Figs. 2-3, 5-15, 18-21, 27, and 29). The treatment results in modulation of expression and/or activity of one or more CYP genes (para [0013], Figs. 10, 12). Shalek teach methods of separating liver cells prior to analysis ([0329] Isolation of Primary Hepatocytes and Non-Parenchymal Cells). Shalek’s teach AhR expression is modulated on exposure to APAP (Table 5a, row 11, on pg. 112).
It would have been prima facie obvious to an artisan of ordinary skill in the art before the effective filing date of the claimed invention to have utilized Papageorgiou’s method to treat CYP-toxicity within the experimental system of Shalek into a single method to take advantage of the robust experimental system of APAP toxicity set up by Shalek. Since Shalek’s results show AhR expression is modulated on exposure to APAP, one would see Papageorgiou’s method of repressing AhR as a method for inhibiting cytochrome p450-mediated toxicity in a cell, wherein the toxicity is a result of APAP overdose. The combination of elements: administering isolated nucleic acid molecules encoding miR-375, SEQ ID NO: 1 (miR-375), as taught by Papageorgiou into the experimental system of APAP-toxicity as taught by Shalek put together by the ordinary skilled artisan would result in a method of inhibiting CYP-toxicity wherein the CYP-450-mediated toxicity is a result of APAP overdose either in a cell or subject. All of the claimed elements were disclosed by Papageorgiou and Shalek and one skilled in the art could have combined these prior art elements by known methods, also taught by Shalek, with no change in their respective functions, and the combination would have yielded predictable results i.e., the instant invention. See MPEP 2143 I.(A). Since all references are in the field of providing a therapeutic benefit to overcome CYP-450-mediated toxicity, one of skill in the art would have a reasonable expectation of success in carrying out such a combination.
Thus, Papageorgiou in view of Shalek make obvious instant claims 1 and 2.
Claims 1 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Papageorgiou (Papageorgiou I. et al., Biochem Pharmacol. 2016 Aug 13;117:78–87.) as evidenced by Abdelmonem (Biomedicines. 2024 Jul 2;12(7):1467. ) (Claim 1).
Regarding claim 1, the teachings of Papageorgiou have been discussed above for claim 1 under §102 and are similarly applied.
Regarding claim 6, Papageorgiou teaches administering to a cell an isolated nucleic acid encoding miR-375 as discussed above.
Papageorgiou does not disclose the sequence of miR-375.
However, Papageorgiou teaches miRBase as the compendium of all known miRNAs (pg. 80, left column first para). The sequence of miR-375 within the pre-miRNA disclosed in miRbase are an exact match to instantly disclosed SEQ ID NO: 1. Papageorgiou teach methods of obtaining ready-to-use miR constructs (§2.1 Chemicals and reagents: Precursor miRNAs, mature miRNA mimics, and the respective negative controls (pre-miR miRNA Precursor Negative Control 1 and 2, miRNA mimics negative control 1 and 2), were purchased from Life Technologies (Grand Island, NY)). It would have been prima facie obvious to an artisan of ordinary skill in the art before the effective filing date of the claimed invention to have combined the various elements taught by Papageorgiou into a single composition and use it in a method of treating CYP-450-mediated toxicity. Obtaining the elements: sequence of miR-375 within the pre-miRNA from miRbase by the ordinary skilled artisan would result in the disclosed SEQ ID NO: 1. All of the claimed elements were disclosed by Papageorgiou and the database provided by Papageorgiou and one skilled in the art could have combined these prior art elements by known methods, also taught by Papageorgiou, with no change in their respective functions, and the combination would have yielded predictable results i.e. SEQ ID NO: 1 of the instant invention. See MPEP 2143 I.(A).
Thus, Papageorgiou makes obvious instant claims 1 and 6.
Claims 1, 3-4, 7-8, 11, 50, 60, and 62 are rejected under 35 U.S.C. 103 as being unpatentable over Papageorgiou (Papageorgiou I. et al., Biochem Pharmacol. 2016 Aug 13;117:78–87, ISR) as evidenced by Abdelmonem (Biomedicines. 2024 Jul 2;12(7):1467. ) (Claim 1) as applied to claim 1 above, and further in view of Mueller (US 20180094264, IDS).
Regarding claim 1, the teachings of Papageorgiou have been discussed above for claim 1 under §102 and are similarly applied.Papageorgiou contemplates administration of miR-375 to patients with acute liver failure (ALF) (Thus miR-375 is identified as a novel repressor of UGT1A-mediated hepatic acetaminophen glucuronidation through reduced AhR expression, which could predispose some individuals to increased risk for acetaminophen-induced ALF, last line of abstract).
Papageorgiou does not provide any teachings of administering the isolated nucleic acid molecule encoding miR-375 to a human subject (claims 3-4 and 62), the isolated nucleic acid molecule encoding miR-375 is an amiRNA (claims 7), in an AAV with ITR (claims 8), or having an AAV8 capsid (claims 11).
However, before the effective filing date of instant application, Mueller taught methods and compositions comprising administering miRNAs to treat human diseases (title). Mueller’s method comprises an artificial microRNA (amiRNA) comprising a miRNA backbone flanking an isolated nucleic acid encoding an miR molecule (para [0004]: Aspects of the disclosure relate to compositions and methods useful for treating Huntington's disease (HD). In some embodiments, inhibitory nucleic acids (e.g., miRNAs, such as artificial miRNAs) are provided that hybridize specifically to and inhibit expression of human huntingtin (HTT); para [0006]: In some aspects, the disclosure provides an isolated nucleic acid comprising: a first region comprising a first adeno-associated virus (AAV) inverted terminal repeat (ITR), or a variant thereof; and, a second region comprising a transgene encoding one or more miRNAs).
Regarding claim 3, Mueller taught the rAAV vector may be delivered to a subject such as a human (paras [0101] –[0125]).
Regarding claim 4, Mueller taught the rAAV vector may have regulatory sequences that impart tissue-specific gene expression capabilities, such as expression in the liver (para [0083).
Regarding claim 7, Mueller taught the isolated nucleic acid molecule encoding miR-375 is an artificial miRNA (amiRNA) (para [0004]).
Regarding claim 8, Mueller taught the rAAV vector comprising the miRNA is flanked by ITRs (para [0089]: Methods for obtaining recombinant AAVs having a desired capsid protein are well known in the art… a recombinant AAV vector composed of, AAV inverted terminal repeats (ITRs) and a transgene).
Regarding claim 11, Mueller taught the rAAV vector comprising the isolated nucleic acid molecule encoding miR-375 may be encapsidated by AAV8 capsid protein (para [0090]).
Regarding claim 50, Mueller taught the rAAV vector comprising the isolated nucleic acid molecule encoding miR-375 may contain a plurality of miRNAs (para [0070]).
Regarding claim 60, Mueller taught the rAAV vector comprising the isolated nucleic acid molecule encoding a plurality of miR-375 may be encapsidated by AAV8 capsid protein (paras [0070] and [0090]).
Regarding claim 62, Mueller taught the rAAV vector may be delivered to a subject such as a human (paras [0101] –[0125]).
It would have been prima facie obvious to an artisan of ordinary skill in the art before the effective filing date of the claimed invention to have combined the various elements taught by Papageorgiou with the design and vector of Mueller into a single composition to make the isolated nucleic acid molecule encoding miR-375 ready for administration to a human host. The combination of elements: isolated nucleic acid molecule encoding miR-375, SEQ ID NO: 1 (miR-375), as taught by Papageorgiou into an AAV8 vector as taught by Mueller put together by the ordinary skilled artisan would result in an isolated nucleic acid molecule encoding miR-375 that may be administered to a cell or to a human for inhibiting CYP-450-mediated toxicity as a result of APAP overdose such as a patient with ALF. All of the claimed elements were disclosed by Papageorgiou and Mueller and one skilled in the art could have combined these prior art elements by known methods, also taught by Mueller, with no change in their respective functions, and the combination would have yielded predictable results i.e. the instant invention. See MPEP 2143 I.(A). Since all references are in the field of providing miRNAs for therapeutic benefit, one of skill in the art would have a reasonable expectation of success in carrying out such a combination.
Thus, Papageorgiou in view of Mueller make obvious instant claims 1, 3-4, 7-8, 11, 50, 60, and 62.
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
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 1-4, 6-8, 11, 50, 60, and 62 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-42 of copending Application No. 19250325 in view of Papageorgiou (Papageorgiou I. et al., Biochem Pharmacol. 2016 Aug 13;117:78–87, ISR).
Although the claims at issue are not identical, they are not patentably distinct from each other because: claims of the aforementioned patent are also drawn to an isolated nucleic acid molecule encoding an amiR that may be administered to a cell or to a human for inhibiting CYP-450-mediated toxicity as a result of APAP overdose such as a patient with ALF. The claims of the reference application do not require administration of miR-375. However, it would be obvious to one skilled in the art to incorporate administration of miR-375 in the method of the ‘325 patent because Papageorgiou provide ample motivation to do so.
Any additional limitations of the ‘325 claims are encompassed by the open claim language “comprising” found in the instant claims. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
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/SHABANA S MEYERING/Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635