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, claims 1-17, 27-29, 31-36, 50 in the reply filed on 04/06/2026 is acknowledged. Species election of miRNA of SEQ ID NO: 1 is acknowledged.
Claims 38, 40-48 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 04/06/2026.
Claim Rejections - 35 USC § 112
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.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
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 of carrying out his invention.
Claims 1-17, 27-29, 31-35, 50 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treatment of ILD, PF-ILD, IPF, connective tissue disease (CTD)-associated ILD, rheumatoid arthritis ILD, chronic fibrosing hypersensitivity pneumonitis (HP), idiopathic non- specific interstitial pneumonia (iNSIP), unclassifiable idiopathic interstitial pneumonia (IIP), environmental/occupational lung disease, pulmonary hypertension (PH), fibrotic silicosis, systemic sclerosis ILD, does not reasonably provide enablement for treatment of sarcoidosis, fibrosarcoma and a full genus of fibroproliferative disorders or prevention of any disorders or treatment by administering any of inhibitors of miRNAs of SEQ ID NOs: 1-14, 16, 34-36. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The claimed invention is not supported by an enabling disclosure taking into account the Wands factors. In re Wands, 858/F.2d 731, 8 USPQ2d 1400 (Fed. Cir. 1988). In re Wands lists a number of factors for determining whether or not undue experimentation would be required by one skilled in the art to make and/or use the invention. These factors are: the quantity of experimentation necessary, the amount of direction or guidance presented, the presence or absence of working examples of the invention, the nature of the invention, the state of the prior art, the relative skill of those in the art, the predictability or unpredictability of the art, and the breadth of the claim.
The claims are broadly drawn to methods of treatment and prevention of fibroproliferative disorders such as ILD, PF-ILD, IPF, connective tissue disease (CTD)-associated ILD, rheumatoid arthritis ILD, chronic fibrosing hypersensitivity pneumonitis (HP), idiopathic non-specific interstitial pneumonia (iNSIP), unclassifiable idiopathic interstitial pneumonia (IIP), environmental/occupational lung disease, pulmonary hypertension (PH), fibrotic silicosis, systemic sclerosis ILD, sarcoidosis and fibrosarcoma by administering viral vectors encoding specific miRNAs, including inhibitors of miRNAs of SEQ ID NOs: 1-14, 16, 34-36.
Instant claims encompass treatment and prevention of a wide variety of fibroproliferative disorders by administering a variety of specific miRNAs or miRNA inhibitors.
The broadest reasonable interpretation of "prevention" or "preventing" encompasses delay or complete prevention of disease onset. This includes both symptomatic and pre-symptomatic disease.
The broadest reasonable interpretation of "treatment" encompasses any therapeutic intervention which ameliorates symptoms, slows progression, or cures a disease.
The broadest reasonable interpretation of "fibroproliferative disorder" encompasses any disorder which may lead to fibrosis. Wynn (J Pathol., 2008, 214(2): 199-210, cited from IDS) defines fibrosis as, "the overgrowth, hardening, and/or scarring of tissue due to excess deposition of extracellular matrix components including collagen." (see Abstract). Disorders which fall into this genus include, "idiopathic pulmonary fibrosis, liver cirrhosis, systemic sclerosis, progressive kidney disease, and cardiovascular fibrosis" (see Abstract). Major tissues affected by fibrosis as well as disorders which can lead to fibrosis are listed in Table 1. These disorders include, but are not limited to, viral hepatitis, diabetes, macular degeneration, Crohn's disease, Alzheimer's disease, and cancer.
Regarding the non-enabled disorders, per Augsburger (Oncotarget, 2017, Vol. 8, No. 61, pp: 104638-104653, cited from IDS), fibrosarcoma is a "rare, highly malignant tumour of mesenchymal cell origin" (see page 104638). It does not appear to be a fibroproliferative disorder of the lungs. Likewise, according to the American Thoracic Society's Statement of Sarcoidosis (1999, cited from IDS), sarcoidosis is a multisystem disorder of unknown cause(s) which affects the lungs but also affects the liver, spleen, lymph nodes, salivary glands, heart, nervous system, muscles and bones (see page 736). Therefore, these two fibroproliferative disorders appear to have different etiologies and patterns of organ involvement compared to the other recited species of predominantly pulmonary fibroproliferative disorders.
Claims 5-9 are drawn to the method of claim 1 comprising administration of an expression cassette coding any RNA that inhibits the function of any one or more of the miRNAs selected from SEQ ID NOs: 1-14, 16, and 34-36. The broadest reasonable interpretation of "any RNA that inhibits the function" encompasses any RNA oligonucleotide which either directly (e.g., through direct binding of the miRNA) or indirectly (e.g., through binding its mRNA target or preventing its transcription) inhibits the function of a miRNA. Beavers (Adv Drug Deliv Rev. 2015 July 1; 88: 123-137, cited from IDS) review various microRNA inhibitors on page 3, including:
- Anti-miR oligonucleotides which bind and inhibit the activity of the mature miRNA guide strand
- Anti-mIRs which bind and inhibit the activity of the pri- or pre-miRNA
- "Blockmirs" which bind to the miRNA's target mRNA and block miRNA.
Tang (Cancer Letters, 2017, 407, 139e147, cited from IDS) also describes several types of competing endogenous miRNA inhibitors (ceRNAs) such as pseudogene RNAs, IncRNAs, viralRNAs, circRNAs and mRNAs (see section “The advent of the ceRNA hypothesis and its mechanism”).
Zhao (Sci Rep, 2014, 4, 3943: 1-5, cited from IDS) describe using the CRISPR interference system to prevent the expression of miRNAs, thereby inhibiting them. Zhao also teaches inhibition of miRNA targets via CRISPR knockdown (see Abstract).
Therefore, based on the information available in the prior art, the genus of any RNA that inhibits the function of a miRNA encompasses all of the species described by Beavers, Tang and Zhao.
It is also relevant to note that the claims are not limited to any particular subject or delivery to any particular tissue in that subject. Therefore, the claims encompass the administration of the miRNAs and their inhibitors to any subject of any age, to any tissue.
The state of the prior art shows that the genus of RNAs which inhibit miRNA is broad and exhibits significant structural and functional variability and unpredictability. In addition, there is a significant amount of variability and unpredictability in the function of the recited miRNAs.
There is also a significant amount of variability and unpredictability in the scope of fibroproliferative disorders, such that the skilled artisan would not have been able to predict whether a treatment for pulmonary fibroses such as IPF or PF-ILD would be successful throughout the full scope of all fibroproliferative disorders as described above (i.e., cancer, diabetes, viral hepatitis, etc.).
Finally, the art shows that prevention of the onset of fibroproliferative disorders is a nascent technology.
Regarding SEQ ID NOs: 1-14, 16, and 34-36, the miRNA targets for the recited RNAs that inhibit their function, even within this smaller genus there is a significant amount of variability and unpredictability. For example, Chai (Int J Clin Exp Pathol 2016;9(2):464-472, cited from IDS) found that expression of miR-146b (instant SEQ ID NO: 16; see Fig. 5 of the specification and note the same sequence in Figure 5 of Chai) increased significantly in pulmonary fibrosis (see page 469) and that it may inhibit fox03 expression to facilitate pulmonary fibrosis (p. 471, Conclusion). However, in their conclusion (see page 471) they caution that:
Although miRNAs have the potential in the therapy of diseases, it has a long way to go before anti-fibrotic therapy is conducted targeting miR-146b. In the inflammation related to interstitial lung diseases, which inflammation related signaling pathway is mainly regulated by miR-146 and the clinical significance of this pathway are largely unclear. In addition, whether increased miR-146 expression in the inflammation may further induce fibrosis and whether inhibition of miR-146 expression may deteriorate inflammation are still needed to be elucidated. There is evidence showing that the miRNA expressing profile is different between fibrotic tissues, which might be helpful for the prediction of fibrosis in different tissues. Currently, most studies on miR-146 are observational, and more studies are required before the application of miR-146 as a target in the therapy of PF.
What this indicates is that even within the genus of the recited miRNAs intended for inhibition, there is considerable variability and unpredictability regarding their role in fibroproliferative disorders, with that role largely unexplored and, insofar as it has been explored, unclear.
Concerning fibroproliferative disorders Rosenbloom (Rosenbloom et al. Human Fibrotic Diseases: Current Challenges in Fibrosis Research. (2017). Laure Rittié (ed.), Fibrosis: Methods and Protocols, Methods in Molecular Biology, vol. 1627, cited from IDS) states that the "causative mechanisms [of fibrotic disease] are quite diverse and in several instances have remained elusive" (see Abstract). They also note that the field of fibrosis research and therapy faces several challenges, including, "incomplete knowledge of the fibrotic process pathogenesis, the marked heterogeneity in their etiology and clinical manifestations, the absence of appropriate and fully validated biomarkers, and, most importantly, the current void of effective disease-modifying therapeutic agents" (see Abstract). The breadth of involved diseases is consistent with Wynn's disclosures above. The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art (MPEP 2164.03). Given the diverse causative mechanisms of fibroproliferative disorders, incomplete knowledge of the pathogenic process, the marked heterogeneity in their etiology, and the current void of disease-modifying therapeutic agents, there are many unknowns as well as a high level of unpredictability with regard to both prevention and treatment of fibroproliferative disorders in general, and a correspondingly increased amount of disclosure to enable the use of the claimed method/mimics.
Instant specification discloses that in both human lung fibroblasts and a mouse model of pulmonary fibrosis, administration of various combinations of miRNA mimics of miR-181a, miR-181b, miR-212-3p, miR-10a, and miR-212-5p demonstrated anti-inflammatory, anti-proliferative and anti-fibrotic effects (see Examples). The specification does not disclose the same effects in any other model of fibrosis in any other organ system. The specification also does not disclose any working examples of RNA inhibition of miRNAs comprising SEQ ID NOs: 1-14, 16, or 34-36.
To use the invention as claimed, at a minimum, the skilled artisan would need to:
- Test miRNA mimetics comprising or consisting of SEQ ID NOs: 17-19 and/or 99-101 at least in models of the full scope of all fibroproliferative disorders throughout the full scope of all organs and subjects.
- Test the full scope of all artificial RNA inhibitors of miRNA to determine if they are able to inhibit the miRNAs comprising SEQ ID NOs: 1-14, 16, or 34-36, and to further test those inhibitors as above with the mimetics throughout the full scope of the claimed disorders, organs, subjects, etc.
- Discover the full scope of all naturally occurring ceRNAs which may inhibit miRNAs comprising SEQ ID NOs: 1-14, 16, or 34-36 and test those throughout the scope of disorders described above.
Taking into consideration the factors outlined above, including the nature of the invention, the breadth of the claims, the state of the art, the guidance provided by the specification, and the amount of experimentation required, it is the conclusion that an undue amount experimentation would be required to make and use the invention as claimed.
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 15 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.
Regarding claim 15, the phrase "preferably" renders the claim indefinite because it states an example or preference. As a consequence, it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Amending the claim to delete the term "preferably" would obviate this rejection.
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.
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.
Claim(s) 1, 2, 10-17, 27, 50 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al (Am J Respir Crit Care Med, 2018, 197:A4616, page 1) and in further view of Strobel et al (Am J Respir Cell Mol Biol, 2015, Vol 53, Issue 3, pp 291-302), Trepel et al (US 2016/0175389, June 2016, cited from IDS), Sah et al (WO 2017/201248, November 2017) and Sindi et al (JOURNAL OF VASCULAR RESEARCH., 2017, Vol. 54., Abstract PoB-77, page 72.)
Chen teach that administration of miR-212-5p, which comprises instant SEQ ID NO: 99 according to instant specification paragraph [0060], in vivo alleviates pulmonary hypertension (see Abstract).
Chen do not teach administration of the miRNA using viral vector of AAV-2 or AASV6.2 serotype comprising capsid comprising SEQ ID NOs: 29, 30 or 82, or administration in combination with miR-181-5p of SEQ ID NO: 17 according to instant specification paragraph [0060], or administration of double-stranded or single-stranded nucleic acid.
Strobel teach viral vectors such as AAV-2 and AAV6.2 for lung gene transfer (see Abstract, page 292).
Trepel teach viral vectors for treatment of lung disorders (see Abstract), including recombinant viral vector rAAV2-ESGHGYF, in which the peptide sequence ESGHGYF is expressed as a partial sequence of the capsid protein VP1 (see paragraph [0013]), such sequence comprising instant SEQ ID NOs: 29 and 30.
Sah teach delivery of single-stranded and double-stranded miRNAs using adeno-associated viruses (AAV) (see paragraphs [0003-0004, 0079]), which can be of AAV-2 serotype (see paragraph [00682]) or AAV6.2 serotype (see paragraph [00691]) and of SEQ ID NO: 130 (see paragraph [00717], Table 4 on page 102), identical to instant SEQ ID NO: 82.
Sindi teach administration of miR-181a-5p for treatment of pulmonary hypertension (see Abstract).
It would have been obvious to one of the ordinary skill in the art before the effective filing date of the claimed invention to administer miR-212-5p and miR-181-5p for treatment of pulmonary hypertension based on teachings of Chen and Sindi using viral vectors taught by Strobel, Trepel and Sah, arriving at instant invention. One of the ordinary skill in the art would be motivated to do so, because Chen and Sindi teach administration of the miRNAs for the treatment of the same fibroproliferative disease, pulmonary hypertension, and Strobel, Trepel and Sah teach effective viral vectors for delivery of miRNAs.
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 1-17, 27-29, 31-36, 50 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2-6, 8-10, 12-13, 16-22, 26, 28-30, 32-42, 45-48, 50 of copending Application No. 17/608328 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because claims from ‘328 recite methods of treatment of IPF and PF-ILD by administering the same miRNAs as in instant invention such as miR-212-5p, miR-181a-5p and miR-181b-5p.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-17, 27-29, 31-36, 50 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17, 27-29, 31-35, 49 of copending Application No. 18/251571 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because claims from ‘571 recite methods of treatment of IPF, ILD and PF-ILD by administering the same miRNAs as in instant invention such as miR-212-5p, miR-181a-5p and miR-181b-5p, using identical fragments of such miRNAs.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-17, 27-29, 31-36, 50 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-17, 19-21, 23-35, 37, 39-49 of copending Application No. 18/251597 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because claims from ‘328 recite methods of treatment of IPF, ILD and PF-ILD by administering the same miRNAs as in instant invention such as miR-212-5p and miR-181a-5p.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
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/EKATERINA POLIAKOVA-GEORGANTAS/Primary Examiner, Art Unit 1637
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