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 07/09/2025. Claims 2-6, 8-10, 12-13, 16-22, 26, 28-30, 32-42 and 45-48 are currently pending.
Election/Restrictions
Applicant's election with traverse of the invention of Group 2 and SEQ ID NO: 15 in the reply filed on 07/09/2025 is acknowledged. The traversal is made only insofar as claim 48, which is drawn to a method of treating diseases comprising administration of a miRNA mimetic, belongs with Group 2. This is found persuasive because claim 48 recites a method of treating the same diseases as those recited in claim 26, using at least a miRNA comprising elected SEQ ID NO: 15. Claim 48 is rejoined and examined herein.
In view of the prior art, which does not teach or suggest a method of treating the specific recited diseases in claim 26 using a miRNA mimetic comprising SEQ ID NO: 15, the provisional election of species of 04/29/2025 has been withdrawn. The non-elected species of SEQ ID NOs: 17, 18 and 19 are searched and examined herein, and claims 8-10, which recite the non-elected species, are rejoined and examined (MPEP 803.02(III)(C)(2)).
In light of the teachings of Xu, Bhattacharyya, and Strobel, the restriction between Group 2, methods of treating diseases, and Group 1, viral vectors, is withdrawn. As discussed in the rejections of the claims under 35 U.S.C. 103 below, the prior art clearly teaches the method comprising delivery of the miRNA using viral vectors and pharmaceutical compositions comprising them. Claims 12-13, 16, 28-30 and 45-47, which read on Group 2, are rejoined and examined herein.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 32-42 and 45-47 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature without significantly more.
Claim 32 recites a miRNA mimetic for use in a method of prevention and/or treatment of a fibroproliferative disorder, wherein the miRNA comprises the sequence of SEQ ID NO: 15. The phrase, “for use in a method of prevention and/or treatment” is a statement of intended use, but does not set forth any structural limitations not present in the body of the claim. Per MPEP 211.02.II, “where a patentee defines a structurally complete invention in the claim body and uses the preamble only to state a purpose or intended use for the invention, the preamble is not a claim limitation”.
Eligibility Analysis:
Eligibility Step 1 (MPEP 2106.03): Is the claim drawn to a statutory category.
The claim is to a composition of matter, a miRNA comprising the sequence of SEQ ID NO: 15, and is eligible at Step 1.
Eligibility Step 2A Prong One (MPEP 2106.04(II)(A)(1)): Is the claim directed to a judicial exception?
The claim is directed to a naturally occurring miRNA sequence. The specification discloses that SEQ ID NO: 15 is miRNA 212-5p (p. 21 ln 20-21). As evidenced by the instant specification, miRNA 212-5p (i.e., a miRNA comprising SEQ ID NO: 15) is a naturally occurring miRNA identified by gene expression analysis (see e.g. Fig. 5 and p. 38 ln 4-8, ln 15-20). This is also evidenced by NCBI Reference Sequence NR_029625.1 (Homo sapiens microRNA 212 (MIR212), microRNA. 06-JAN-2019.), which is the coding sequence for the human miR-212 precursor RNA and comprises the claimed sequence at positions 31-53. Please note that, per the “FEATURES” section for NR_029625.1, positions 31-53 are the mature miR-212-5p guide sequence. While the specification defines the term “miRNA mimetic” as, “an oligomer capable of specifically increasing the activity of Certain (mainly downregulated) miRNA” (p. 28 ln 21-22), the definition does not exclude the naturally occurring miRNA because the miRNA is, in and of itself, an oligomer capable of increasing (or carrying out) its own activity.
The claim is not eligible at Step 2A Prong 1.
Eligibility Step 2A Prong One: (MPEP 2106.04(c)): Are the structural characteristics of the claimed miRNA markedly different from its closest naturally occurring counterpart?
The claim recites no additional structural elements beyond SEQ ID NO: 15. This structure is shared in its entirety with the closest naturally occurring counterpart, the mature guide sequence of miRNA-212/NR_029794.1.
The claim is not eligible according to the markedly different characteristics analysis.
Eligibility Step 2A Prong Two (MPEP 2106.04(d)): Does the claim integrate the exception into a practical application?
Because the intended use does not further define the structure and is thus non-limiting (MPEP 211.02.II.), the claim does not integrate the exception into a practical application.
The claim is ineligible at Step 2A Prong Two.
Eligibility Step 2B (MPEP 2106.05): The claim(s) does not include additional
elements that are sufficient to amount to significantly more than the judicial exception.
The claim is ineligible at Step 2B.
Claims 33, 36 and 38 recite optional chemical modifications and/or nucleotide analogues and/or lipid conjugates. However, these limitations are optional, i.e., not required. The claims also limit the sequences to ones “consisting of” SEQ ID NOs: 15, 17, 18, and/or 19. However, according to Shukla (Shukla et al. MicroRNAs: Processing, Maturation, Target Recognition and Regulatory Functions. Mol Cell Pharmacol. 2011 ; 3(3): 83–92.), microRNAs are naturally processed into guide strands (i.e., oligomers consisting of the mature guide sequences, such as miRNA-212a-5p) in the cell and form part of the RISC+guide complex (see e.g. Figure 4A). Therefore, oligomers consisting of the guide strand sequences are naturally occurring, and the claims do not recite any structural elements beyond those sequences that might differentiate the claimed miRNAs from their naturally occurring counterparts.
Claims 34-35, 37, and 39-42 all recite additional miRNAs comprising SEQ ID NOs: 17, 18 and/or 19. However, these are also naturally occurring miRNAs. See p. 21 ln 20-22, which states that SEQ ID NO: 17 is mir-181a-5p, SEQ ID NO: 18 is miR-10a, and SEQ ID NO: 19 is miR-181b-5p. See also NCBI Reference Sequences NR_029611.1, NR_029608.1, and NR_029612.1, which comprise SEQ ID NOs: 17, 18 and 19, respectively. Please note, as well, that all of these reference sequences occur in the human genome. Therefore, all of the encoded miRNAs may naturally be expressed and present in combination in a human cell. The claims do not add any structural elements to differentiate those miRNAs from their naturally occurring counterparts.
Claim 42 limits the disorder, but, as discussed above, the intended use preamble is non-limiting.
Regarding claims 45-47, these are ineligible for the reasons discussed above. While these claims recite the additional limitation of a pharmaceutical carrier, please note that the term “pharmaceutically acceptable carrier” is interpreted as encompassing water, which is present in cells. Therefore, the claims encompass cells comprising naturally expressed miRNAs.
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.
Claim 22 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 22, 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
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.
Claim 48 is rejected under 35 U.S.C. 103 as being unpatentable over Xu (Xu et al. High glucose down-regulates microRNA-181a-5p to increase pro-fibrotic gene expression by targeting early growth response factor 1 in HK-2 cells. Cellular Signalling, Elsevier Science, 2017, vol. 31, pages 96-104.; applicant’s submission) in view of Bhattacharyya (Bhattacharyya et al. Early growth response transcription factors: Key mediators of fibrosis and novel targets for anti-fibrotic therapy. Matrix Biology. Volume 30, Issue 4, May 2011, Pages 235-242.).
Xu teaches a method of treating a fibroproliferative disorder (renal tubulointerstitial fibrosis or TIF) with a vector comprising a miRNA-181a-5p mimic (p. 97 §2.5). The specification discloses that instant SEQ ID NO: 17 is the miRNA 181a-5p sequence (p. 21 ln 21).
Xu further teaches that Egr1 plays a crucial role in TIF progression (§ABSTRACT), and that miR-181a-5p alleviates Egr1-induced fibrosis in HK-2 cells (§3.5) by directly suppressing Egr1 to decrease the expression of TGF-β1, fibronectin and collagen I (§ABSTRACT).
Xu does not teach the method of treating the fibroproliferative disorders recited in claim 26.
Bhattacharyya teaches that aberrant Egr1 is a key mediator of fibrosis and a target for anti-fibrotic therapy (Title). Bhattacharyya further teaches that fibrosis in various human diseases and animal models such as scleroderma and idiopathic pulmonary fibrosis (IPF) is accompanied by aberrant Egr1 expression, and that Egr-1-null mice are protected from fibrosis (§ABSTRACT).
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 Xu and Bhattacharyya to obtain a method of treating IPF and other fibrotic disorders via administration of a miR-181a-5p mimic to a subject. The skilled artisan would have been motivated to use miR-181a-5p as a treatment for fibrotic disorders based Xu’s teachings that miR-181a-5p alleviated Egr1-induced renal fibrosis, combined with Bhattacharyya’s teachings that Egr1 is a key mediator of fibrosis in multiple fibrotic disorders in other tissues, such as the skin (scleroderma) and lungs (IPF). Based on Bhattacharyya’s teachings that Egr1 is a key mediator of fibrosis in multiple disorders, the skilled artisan would have predicted, with a reasonable expectation of success, that Xu’s method of alleviating Egr1-induced TIF by administration of a miR-181a-5p mimic to inhibit Egr1 expression would have been applicable to other Egr1-induced fibroses, such as IPF.
Claims 17-18, 22, 26 and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Xu (Xu et al. High glucose down-regulates microRNA-181a-5p to increase pro-fibrotic gene expression by targeting early growth response factor 1 in HK-2 cells. Cellular Signalling, Elsevier Science, 2017, vol. 31, pages 96-104.; applicant’s submission) in view of Bhattacharyya (Bhattacharyya et al. Early growth response transcription factors: Key mediators of fibrosis and novel targets for anti-fibrotic therapy. Matrix Biology. Volume 30, Issue 4, May 2011, Pages 235-242.) and Strobel (Strobel et al. Modeling Pulmonary Disease Pathways Using Recombinant Adeno-Associated Virus 6.2. Am J Respir Cell Mol Biol Vol 53, Iss 3, pp 291–302, Sep 2015.).
Xu teaches a method of treating a fibroproliferative disorder (renal tubulointerstitial fibrosis or TIF) with a vector comprising a miRNA-181a-5p mimic (p. 97 §2.5). The specification discloses that instant SEQ ID NO: 17 is the miRNA 181a-5p sequence (p. 21 ln 21).
Xu further teaches that Egr1 plays a crucial role in TIF progression (§ABSTRACT), and that miR-181a-5p alleviates Egr1-induced fibrosis in HK-2 cells (§3.5) by directly suppressing Egr1 to decrease the expression of TGF-β1, fibronectin and collagen I (§ABSTRACT).
Xu does not teach the method of treating the specific fibroproliferative disorders recited in claim 26.
Bhattacharyya teaches that aberrant Egr1 is a key mediator of fibrosis and a target for anti-fibrotic therapy (Title). Bhattacharyya further teaches that fibrosis in various human diseases and animal models such as scleroderma and idiopathic pulmonary fibrosis (IPF) is accompanied by aberrant Egr1 expression, and that Egr-1-null mice are protected from those types of fibrosis (§ABSTRACT).
Neither Xu nor Bhattacharyya teach delivery of the miRNA via a viral vector.
Strobel teaches AAV variant 6.2 as “an ideal vector for lung delivery” (§Abstract).
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 Xu, Bhattacharyya and Strobel to obtain a method of treating IPF and other fibrotic disorders via viral delivery of miR-181a-5p mimics to a subject. The skilled artisan would have been motivated to use miR-181a-5p as a treatment for fibrotic disorders based Xu’s teachings that miR-181a-5p alleviated Egr1-induced renal fibrosis, combined with Bhattacharyya’s teachings that Egr1 is a key mediator of fibrosis in multiple fibrotic disorders in other tissues, such as the skin (scleroderma) and lungs (IPF). Based on Bhattacharyya’s teachings that Egr1 is a key mediator of fibrosis in multiple disorders, the skilled artisan would have predicted, with a reasonable expectation of success, that Xu’s method of alleviating Egr1-induced TIF by administration of a miR-181a-5p mimic to inhibit Egr1 expression would have applied to other Egr1-induced fibroses, such as IPF. Regarding the viral vector, the skilled artisan would further have been motivated to use Strobel’s AAV6.2 vector as a delivery vehicle for the method of treating IPF as taught by the combination of Xu and Bhattacharyya based on Strobel’s express teaching that AAV6.2 is ideal for delivering gene therapy to the lungs.
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Xu in view of Bhattacharyya and Strobel, as applied to claims 17-18, 26 and 28 above, further in view of U.S. PGPUB 2016/0175389 A1 to Trepel (hereinafter ‘Trepel’; note that this is also published as WO 2015/018860 A1, applicant’s own submission).
Xu, Bhattacharyya and Strobel, render obvious the method of claim 26, from which claim 19 depends, as described above.
Xu, Bhattacharyya and Strobel, do not teach wherein the capsid comprises a first protein that comprises the sequence of SEQ ID NO: 29 or 30.
Trepel teaches a recombinant viral vector rAAV2-ESGHGYF in which SEQ ID NO: 30 (i.e., Trepel’s SEQ ID NO: 2, EGHGYF) with a core structure of SEQ ID NO: 29 (Trepel’s SEQ ID NO: 1, GHGYF) is expressed as part of the capsid protein VP1 (para [0013]).
Trepel further teaches that the vector comprising those capsid sequences had, “a unique specificity of the vector for lung endothelial tissue was observed both in vitro and in vivo” (Id.) and were, “particularly suited for directing therapeutic agents such as viral vectors to the lungs of a subject being treated” (para [0014]).
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 the method of treating IPF by administering a AAV vector comprising miRNA 181a-5p, as taught by Xu, Bhattacharyya and Strobel, by altering the vector’s VP1 capsid sequence to give it a unique specificity for lung endothelial tissue, as taught by Trepel. Based on Trepel’s teachings, the skilled artisan would have predicted, with a reasonable expectation of success, that this would have yielded a gene therapy treatment particularly suited for directing the therapeutic treatment to the lung of the subject being treated.
Claim 22 is rejected under 35 U.S.C. 103 as being unpatentable over Xu (Xu et al. High glucose down-regulates microRNA-181a-5p to increase pro-fibrotic gene expression by targeting early growth response factor 1 in HK-2 cells. Cellular Signalling, Elsevier Science, 2017, vol. 31, pages 96-104.; applicant’s submission) in view of Bhattacharyya (Bhattacharyya et al. Early growth response transcription factors: Key mediators of fibrosis and novel targets for anti-fibrotic therapy. Matrix Biology. Volume 30, Issue 4, May 2011, Pages 235-242.), Strobel (Strobel et al. Modeling Pulmonary Disease Pathways Using Recombinant Adeno-Associated Virus 6.2. Am J Respir Cell Mol Biol Vol 53, Iss 3, pp 291–302, Sep 2015.), and U.S. Patent No. 10,584,337 to Sah (priority filing date 05/18/2016, hereinafter ‘Sah’).
Xu, Bhattacharyya and Strobel render obvious the method of claim 26, from which claim 22 depends, as described above.
Xu, Bhattacharyya and Strobel do not teach wherein the capsid comprises a capsid protein having the sequence of SEQ ID NO: 82.
Hoever, Strobel teaches AAV variant 6.2 as “an ideal vector for lung delivery” (§Abstract).
Sah teaches SEQ ID NO: 130, which is 100% identical to SEQ ID NO: 82. See the following alignment:
RESULT 1
SEQIDNO130
Query Match 100.0%; Score 3990; DB 1; Length 736;
Best Local Similarity 100.0%;
Matches 736; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDDGRGLVLPGYKYLGPFNGLD 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDDGRGLVLPGYKYLGPFNGLD 60
Qy 61 KGEPVNAADAAALEHDKAYDQQLKAGDNPYLRYNHADAEFQERLQEDTSFGGNLGRAVFQ 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 KGEPVNAADAAALEHDKAYDQQLKAGDNPYLRYNHADAEFQERLQEDTSFGGNLGRAVFQ 120
Qy 121 AKKRVLEPLGLVEEGAKTAPGKKRPVEQSPQEPDSSSGIGKTGQQPAKKRLNFGQTGDSE 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 AKKRVLEPLGLVEEGAKTAPGKKRPVEQSPQEPDSSSGIGKTGQQPAKKRLNFGQTGDSE 180
Qy 181 SVPDPQPLGEPPATPAAVGPTTMASGGGAPMADNNEGADGVGNASGNWHCDSTWLGDRVI 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 SVPDPQPLGEPPATPAAVGPTTMASGGGAPMADNNEGADGVGNASGNWHCDSTWLGDRVI 240
Qy 241 TTSTRTWALPTYNNHLYKQISSASTGASNDNHYFGYSTPWGYFDFNRFHCHFSPRDWQRL 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 TTSTRTWALPTYNNHLYKQISSASTGASNDNHYFGYSTPWGYFDFNRFHCHFSPRDWQRL 300
Qy 301 INNNWGFRPKRLNFKLFNIQVKEVTTNDGVTTIANNLTSTVQVFSDSEYQLPYVLGSAHQ 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 INNNWGFRPKRLNFKLFNIQVKEVTTNDGVTTIANNLTSTVQVFSDSEYQLPYVLGSAHQ 360
Qy 361 GCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSFYCLEYFPSQMLRTGNNFTFSYTFEDVP 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 GCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSFYCLEYFPSQMLRTGNNFTFSYTFEDVP 420
Qy 421 FHSSYAHSQSLDRLMNPLIDQYLYYLNRTQNQSGSAQNKDLLFSRGSPAGMSVQPKNWLP 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 FHSSYAHSQSLDRLMNPLIDQYLYYLNRTQNQSGSAQNKDLLFSRGSPAGMSVQPKNWLP 480
Qy 481 GPCYRQQRVSKTKTDNNNSNFTWTGASKYNLNGRESIINPGTAMASHKDDKDKFFPMSGV 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 GPCYRQQRVSKTKTDNNNSNFTWTGASKYNLNGRESIINPGTAMASHKDDKDKFFPMSGV 540
Qy 541 MIFGKESAGASNTALDNVMITDEEEIKATNPVATERFGTVAVNLQSSSTDPATGDVHVMG 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 MIFGKESAGASNTALDNVMITDEEEIKATNPVATERFGTVAVNLQSSSTDPATGDVHVMG 600
Qy 601 ALPGMVWQDRDVYLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPPA 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 601 ALPGMVWQDRDVYLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPPA 660
Qy 661 EFSATKFASFITQYSTGQVSVEIEWELQKENSKRWNPEVQYTSNYAKSANVDFTVDNNGL 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 661 EFSATKFASFITQYSTGQVSVEIEWELQKENSKRWNPEVQYTSNYAKSANVDFTVDNNGL 720
Qy 721 YTEPRPIGTRYLTRPL 736
||||||||||||||||
Db 721 YTEPRPIGTRYLTRPL 736
Sah teaches compositions comprising artificial microRNAs, encoded by or within recombinant adeno-associated viruses (AAV) (col 1 ln 26-31).
Sah further teaches that the artificial microRNAs may be encoded in any of the AAVs in Table 5, including AAV serotype 6.2, SEQ ID NO: 130 (col 75-76).
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 the combined teachings of Xu, Bhattacharyya and Strobel by encoding the miRNA of SEQ ID NO: 17 into an AAV6.2 serotype expression vector comprising SEQ ID NO: 130. The skilled artisan would have been motivated in particular by a combination of Strobel’s teachings that AAV6.2 was an ideal vector for delivery of gene therapy to the lungs and Sah’s teachings that SEQ ID NO: 130 was a suitable vector for artificial miRNAs. The combination would predictably have yielded a viral vector suitable for delivery of artificial miRNAs to the lungs to treat pulmonary fibroses.
Claim Rejections - 35 USC § 112(a) – Scope of Enablement
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 2-6, 8-10, 12-13, 16-22, 26, 28-30, 32- and 45-48 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:
methods of using the claimed miRNA mimetics comprising SEQ ID NOs: 15, 17, 18, 19, and combinations thereof for treatment of 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, systemic sclerosis ILD
methods of using SEQ ID NO: 17 to treat Egr1-induced renal fibrosis
The specification does not reasonably provide enablement for:
preventing IPF or PF-ILD
treating all disorders within the genus of fibroproliferative disorders
treating all disorders within the genus of fibroproliferative disorders
treating sarcoidosis or fibrosarcoma
treating any of the claimed disorders using an RNA that inhibits the function of one or more miRNAs selected from the group consisting of miRNAs of SEQ ID NOs: 1-14, 16, and 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.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (CA FC 1988). Wands states at page 1404,
“Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex part Forman. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.”
The nature of the invention
Claim 32 is drawn to a miRNA mimetic for use in a method of prevention and/or treatment of a fibroproliferative disorder The invention is the class of invention that the CAFC has characterized as “the unpredictable arts such as chemistry and biology”. Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F. 3d 1316 (Fed. Cir. 2001).
The breadth of the claims
Claim 32 encompasses prevention and/or treatment of all fibroproliferative disorders.
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 (Wynn. Cellular and molecular mechanisms of fibrosis. J Pathol. 2008 Jan;214(2):199–210.) defines fibrosis as, “the overgrowth, hardening, and/or scarring of tissue due to excess deposition of extracellular matrix components including collagen.” (§Abstract). Disorders which fall into this genus include, “idiopathic pulmonary fibrosis, liver cirrhosis, systemic sclerosis, progressive kidney disease, and cardiovascular fibrosis” (Id.). 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 (Augsburger et al. Current diagnostics and treatment of fibrosarcoma –perspectives for future therapeutic targets and strategies. Oncotarget, 2017, Vol. 8, (No. 61), pp: 104638-104653.), fibrosarcoma is a, “rare, highly malignant tumour of mesenchymal cell origin”. It does not appear to be a fibroproliferative disorder of the lungs. Likewise, according to the American Thoracic Society’s Statement of Sarcoidosis (1999), 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 (p. 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 12-13 and 16 are drawn to the method of claim 26 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 (Beavers et al. miRNA Inhibition in Tissue Engineering and Regenerative Medicine. Adv Drug Deliv Rev. 2015 July 1; 88: 123–137.) review various microRNA inhibitors, including:
Anti-miR oligonucleotides which bind and inhibit the activity of the mature miRNA guide strand (§Artificial miRNA inhibitors §§Anti-miRNA oligonucleotides)
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 binding sites
Tang (Tang et al. microRNA inhibitors: Natural and artificial sequestration of microRNA. Cancer Letters 407 (2017) 139e147.) also describes several types of competing endogenous miRNA inhibitors (ceRNAs) such as pseudogene RNAs, lncRNAs, viralRNAs, circRNAs and mRNAs (§The advent of the ceRNA hypothesis and its mechanism).
Zhao (Zhao et al. Sequence-specific inhibition of microRNA via CRISPR/CRISPRi system. Sci Rep 4, 3943 (2014).) 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. (§Abstract).
Therefore, based on the information available in the prior art, the genus of any RNA that inhibits the function of an 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 unpredictability of the art and the state of the prior art
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 RNA inhibitors of miRNA:
As discussed above, the claims encompass several types of RNA inhibitors of miRNA, which vary both structurally and functionally. Per Tang, these include naturally occurring RNAs such as pseudogene RNAs, lncRNAs, viralRNAs, circRNAs and mRNAs. All of these different kinds of RNAs, termed “competing endogenous RNAs (ceRNA)” (p. 140), “…can sequestrate miRNA and act as ceRNA. However, their activity is influenced and regulated by multiple factors, including the relative abundance of ceRNA, miRNA and target mRNA; the stability of ceRNA; and the subcellular localization of ceRNA/miRNA.” (p. 142 §Factors that influence ceRNA activity). This points to a significant degree of complexity, variability and unpredictability within the system of ceRNAs and their interactions with their target miRNAs and each other. In particular, Tang notes that, “the function and regulatory mechanisms of circRNAs remain elusive” (p. 141).
Regarding the miRNAs:
While the scope of the claimed miRNAs and their RNA inhibitors is limited, the scope of their functions is broad, encompassing treatment of any fibroproliferative disorder in any subject or tissue.
The state of the art prior to the filing date of the instantly claimed invention shows that the expression and function of miRNAs vary widely among organs, tissues and species, as evidenced by Ha et al. (Biochim Biophys Acta. 2008 Nov;1779(11):735-42) and Banzhaf-Strathmann and Edbauer (Cell Commun Signal 12, 30 (2014)). Ha discloses that, as of 2008, thousands of miRNAs had been identified in animals and plants (with the majority found in animals), and estimates indicate that 1-5% of the transcribed genes in animals contain miRNAs (p. 2).
The above evidences that the scope of all miRNAs in animals is vast. Within that scope, Ha further discloses that many miRNAs are species- and/or tissue-specific, and that the expression patterns of animal miRNAs is varied and thus, difficult to predict even when the miRNA sequences are conserved among species: Conserved miRNAs do not necessarily exhibit the same expression levels or patterns in different species or at different stages within a species, even though the sequences of mature miRNAs are generally conserved in the animal kingdom. [abstract]
Major miRNA renovations occurred at the emergence of vertebrates and placental mammals. Many miRNAs, such as miR-126 and miR-206, are expressed in vertebrate-specific organs. Moreover, ∼42% of the 800 primate miRNAs are primate-specific and are absent in other mammals…477 new miRNA genes in the brains of humans and chimpanzee. Among all small RNAs cloned, 75% were known human and primate miRNAs, 14% were conserved in vertebrates, 10% were primate-specific, and 1% were human specific. [p. 3]
Although sequence conservation of miRNAs and target genes may suggest conservation of expression patterns and functions, this assumption does not hold true for many conserved miRNAs. By comparing expression patterns of ∼100 miRNAs that are conserved in sequences in fish, chicken, and mouse, Ason et al. (2006) indicated that the timing and location of miRNA expression is not strictly conserved [107]. Several conserved miRNAs such as miR-454a, miR-145, and miR-205 clearly displayed spatial expression differences between two closely related species, medaka and zebrafish. It is conceivable that the spatial and temporal regulation of conserved miRNAs may also play an important role in shaping developmental and physiological changes during animal evolution. [p. 4]
Therefore, Ha shows that there is a high level of variability in and unpredictability of miRNA expression through the full scope of animal subjects.
When we narrow the scope even to a single miRNA in a single species, Banzhaf-Strathmann and Edbauer provide an example wherein the expression of said miRNA varies by tissue:
One miRNA that has gained special interest in the field of cancer research is miRNA- 125b (miR-125b). MiR-125b is a ubiquitously expressed miRNA that is aberrantly expressed in a great variety of tumors. In some tumor types, e.g. colon cancer and hematopoietic tumors, miR-125b is upregulated and displays oncogenic potential, as it induces cell growth and proliferation, while blocking the apoptotic machinery. In contrast, in other tumor entities, e.g. mammary tumors and hepatocellular carcinoma, miR-125b is heavily downregulated. This downregulation is accompanied by de-repression of cellular proliferation and anti-apoptotic programs, contributing to malignant transformation. The reasons for these opposing roles are poorly understood. [abstract].
Therefore, Banzhaf-Strathmann and Edbauer evidence further unpredictability of miRNA expression within the full scope of any sample type even when it relates to one miRNA in one species.
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 (Chai et al. miR-146b expression is upregulated in the lung of pulmonary fibrosis mice. Int J Clin Exp Pathol 2016;9(2):464-472.) found that expression of miR-146b (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 (p. 469) and that it may inhibit foxO3 expression to facilitate pulmonary fibrosis (p. 471, Conclusion). However, in their conclusion (p. 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.
Regarding prevention of 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.) states that the, “causative mechanisms [of fibrotic disease] are quite diverse and in several instances have remained elusive” (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” (Id.). 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.
Guidance in the specification and working examples
The 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-p, miR10a, and miR-212-3p demonstrated anti-inflammatory, anti-proliferative and anti-fibrotic effects. 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: 11-14, 16, or 34-36.
The quantity of experimentation
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: 15, 17, 18 and/or 19 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: 11-14, 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: 11-14, 16, or 34-36 and test those throughout the scope of disorders described above.
Conclusion
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.
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.
Claim 2-6, 17-22, 26, 32-39, 42 and 48 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 10-15, 28, 34 and 44-45 of copending Application No. 18251562 in view of Bofill-De Ros (Guidelines for the optimal design of miRNA-based shRNAs. Methods. 2016 July 1; 103: 157–166.).
This is a provisional nonstatutory double patenting rejection because the copending claims have not been patented.
The instant and copending claims are related as follows:
Instant claim
Copending claim
26. Method of treating a disease selected from the group consisting of 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, systemic sclerosis ILD, sarcoidosis, and fibrosarcoma, the method comprising administering to a patient in need thereof a therapeutically active amount of viral vector comprising: a capsid and a packaged nucleic acid, wherein the packaged nucleic acid codes for one or more miRNAs, wherein at least one of the one or more miRNAs comprises the miRNA of Seq ID No. 15, Seq ID No. 17, or Seq ID No. 19.
48. Method of treating a disease selected from the group consisting of 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, systemic sclerosis ILD, sarcoidosis, and fibrosarcoma, the method comprising administering to a patient in need thereof a therapeutically active amount of a pharmaceutical composition comprising (i) a miRNA mimetic of a miRNA having the sequence of Seq ID No. 15, or (ii) a miRNA mimetic of a miRNA having the sequence of Seq ID No. 17, or (iii) a miRNA mimetic of a miRNA having the sequence of Seq ID No. 18, or (iv) a miRNA mimetic of a miRNA having the sequence of Seq ID No. 19, and apharmaceutical-acceptable carrier or diluent.
1. A method of treating or preventing a disease selected from the group consisting 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, sarcoidosis, and fibrosarcoma, the method comprising:administering to a patient in need thereof a therapeutically active amount of viral vector,wherein said viral vector comprises a capsid and a packaged nucleic acid, wherein the packaged nucleic acid codes for one or more miRNAs, wherein the one or more miRNAs comprise the miRNA fragment having the sequence of Seq ID No. 99.
2. The method of claim 26, wherein the packaged nucleic acid codes for more than one miRNA, wherein said miRNAs comprise the miRNA of Seq ID No. 15 and the miRNA of Seq ID No. 19 and a miRNA of Seq ID No. 18.
3. The method of claim 26, wherein the packaged nucleic acid codes for more than one miRNA, wherein said miRNAs comprise the miRNA of Seq ID No. 15 and the miRNA of Seq ID No. 17 and a miRNA of Seq ID No. 18.
4. The method of claim 26, wherein the packaged nucleic acid codes for more than one miRNA, wherein said miRNAs comprise the miRNA of Seq ID No. 15 and the miRNA of Seq ID No. 17 and the miRNA of Seq ID No. 19.
5. The method of claim 26, wherein the packaged nucleic acid codes for more than one miRNA, wherein said miRNAs comprise the miRNA of Seq ID No. 15 and the miRNA of Seq ID No. 17.
6. The method of claim 26, wherein the packaged nucleic acid codes for more than one miRNA, wherein said miRNAs comprise the miRNA of Seq ID No. 15 and the miRNA of Seq ID No. 19.
8. The method of claim 26 wherein the packaged nucleic acid codes for more than one miRNA, wherein said miRNAs comprise the miRNA of Seq ID No. 19 and the miRNA of Seq ID No. 17.
9. The method of claim 26 wherein the packaged nucleic acid codes for more than one miRNA, wherein said miRNAs comprise the miRNA of Seq ID No. 19 and a miRNA of Seq ID No. 18.
10. The method of clai