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 01/23/2023. Claims 1-17 are currently pending and are examined herein.
Specification
The disclosure is objected to because of the following informalities:
The brief descriptions of the figures include references to color, but the application does not contain color drawings. Please see p. 15 ln 6, 15, 24-25, 31-32; p. 16 ln 17-18, 21-22, 25-26; p. 17 ln 8-9, 13, 26, 29.
Appropriate correction is required.
Drawings
The drawings are objected to because of the following minor informalities:
37 CFR 1.84 (u)(1) states “View numbers must be preceded by the abbreviation "FIG."”
In the current case, the view numbers for Figures 1, 2, 6 8 and 10 are preceded by the word "Figure" instead of the abbreviation "FIG.".
37 CFR 1.84 (u)(1) states “Partial views intended to form one complete view, on one or several sheets, must be identified by the same number followed by a capital letter.”
In the current case, the view numbers for the partial views for Figures 1, 2, 6 8 and 10 that appear on several sheets are preceded by the word “figure” and followed by "(continued)." instead of a capital letter such as FIG. 1A, FIG. 1B, 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.
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.
Claim Objections
Claims 2 and 9 are objected to because of the following informalities: Claim 2 contains a period in the body of the claim (“according to claim 1.”). Claim 9 also contains periods in the body of the claim (“microRNAs comprise a. miR-1a, and b. miR-16b). MPEP 608.01(m) states, “Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations.” Amending claim 2 to delete the extra period and amending claim 9 to replace the periods with parentheses (e.g., a[[.]]) ) would obviate this objection. Appropriate correction is required.
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 1-3, 9 and 14-15 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature without significantly more.
Regarding step 1 (MPEP 2106.03), claim 1 recites a combination of nucleic acid agents, wherein each nucleic acid agent is directed at and capable of specifically inhibiting and/or degrading a target microRNA and/or combination of microRNAs within a cell. The combination of microRNAs is either: miR-1a and miR-15b; or miR-1a, miR-15b and miR-27b. The combination of nucleic acid agents is a composition of matter, and eligible at step 1.
Regarding step 2A prong one (MPEP 2106.04), the ‘combination of nucleic acid agents’ refers to a judicial exception because it encompasses naturally-occurring non-coding RNAs which naturally target and inhibit microRNAs and are naturally present in human cells. For example, long-coding RNA SNHG1 is able to directly bind to miR-15b-5p and represses miR-15b-5p expression (Chen et al. LncRNA SNHG1 promotes α-synuclein aggregation and toxicity by targeting miR-15b-5p to activate SIAH1 in human neuroblastoma SH-SY5Y cells. NeuroToxicology, Volume 68, 2018, Pages 212-221.)(Title, Abstract). Similarly, lncRNA Rmrp acts as a sponge for miR-1a-3p, upregulating expression of miR-1a-3p’s target genes (i.e., inhibiting miR-1a-3p) (Yang et al. Sp1-Induced lncRNA Rmrp Promotes Mesangial Cell Proliferation and Fibrosis in Diabetic Nephropathy by Modulating the miR-1a-3p/JunD Pathway. 2021. Front. Endocrinol. 12:690784.)(Abstract, p. 2). The lncRNA MALAT1 functions as a miRNA sponge for multiple miRNAs, including miR-1a (Yuan et al. Long non-coding RNA MALAT1 functions as miR-1 sponge to regulate Connexin 43-mediated ossification of the posterior longitudinal ligament. Bone 127 (2019) 305-314.) and miR-15b (Wheeler et al. The lncRNA Malat1 Inhibits miR-15/16 to Enhance Cytotoxic T Cell Activation and Memory Cell Formation. 2023. eLife12:RP87900.). All of these lncRNAs are naturally expressed by human cells and would be expected to naturally be present at the same time, i.e., in combination. Therefore, the combination of nucleic acid agents is a product of nature, which is a judicial exception (MPEP 2106.04(b)).
Product of nature exceptions are subject to the markedly different characteristics analysis at step 2a prong 1 of the subject matter eligibility analysis (MPEP 2106.04(c)). The markedly different characteristics analysis compares the nature-based product limitation to its closest naturally occurring counterpart and asks whether the claimed product has markedly different structural and/or functional characteristics from its naturally occurring counterpart. In the instant case, the claimed combination of nucleic acid agents is recited at a high level of generality. No structural information is given beyond the fact that they are nucleic acids, so there is no marked difference between the claimed product and the naturally occurring combination of lncRNAs. The naturally occurring lncRNAs also have the recited functional characteristic of being directed at and capable of specifically inhibiting a target microRNA, so the functional characteristics of the claimed products are not markedly different from those of their naturally occurring counterparts. The recitation of the agents being “for use in treatment or prevention of heart disease” is merely a statement of an intended use of the claimed product. The remainder of the claim sets forth a structurally complete product, i.e., the combination of nucleic acid agents. Per MPEP 2111.02, “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”. Therefore, the intended use of the product for treatment or prevention of heart disease is not given patentable weight and is not considered in this analysis.
Regarding steps 2A prong two and step 2B, the claims do not recite additional elements. Therefore, the claims do not recite additional elements that integrate the judicial exception into a practical application (step 2A prong two) or amount to significantly more than the judicial exception (step 2b).
Regarding claims 2-3, these claims are also patent ineligible because they merely recite a specific combination of microRNAs or wherein the nucleic acid agent comprises a hybridizing sequence of nucleotides capable of forming a hybrid (i.e., binding) a target microRNA. As discussed above, the naturally occurring lncRNAs are capable of hybridizing with/binding their target microRNAs.
Claim 4 is eligible because the phrase “comprises…a sequence selected from the sequences SEQ ID NO 001-004” is interpreted as requiring that the nucleic acid agent comprise one of the recited sequence with 100% identity, and none of the naturally occurring lncRNAs listed above comprises those particular sequences.
Claims 5-7 are eligible because they recite wherein at least one of the agents at least comprise one or several LNA or PNA moieties, thiophosphate bonds or combinations thereof, which is a markedly different structural feature compared to the naturally occurring lncRNAs.
Claim 8 is eligible because the agents are expressed from an exogenous expression construct.
Claim 9 is not eligible because the claim is drawn to an expression construct or plurality of expression constructs encoding, under control of a promoter operable in a human myocardial cell, the combination of nucleic acid agents. The instant specification does not provide a clear, explicit definition of the term “expression construct”. The broadest reasonable interpretation of the limitation encompasses a plurality of naturally occurring genes.
Claim 10 is eligible because a search of the art did not show evidence that the naturally occurring lncRNAs are comprised within a single nucleic acid molecule (chromosome).
Claims 11 and 12 are eligible because they require that the combination of nucleic acid agents be bound to a nanoparticle or encapsulated by a virus or liposome.
Claim 13 is eligible because a search of the art did not reveal evidence that the naturally occurring counterparts are normally under control of the recited promoters.
Claims 14-15 are not eligible because they merely recite types of heart disease but do not recite additional elements which integrate the judicial exception into a practical application or amount to significantly more.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 5-10 and 11-14 are rejected under 35 § U.S.C. 112(b) or 35 § U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 5-9 and 11-14 recite the term “particularly”. The term renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Amending the claims to delete the term “particularly” would obviate this rejection.
Claim 7 recites, “a LNA moiety connected to an adjacent by a thiophosphate bond”. The term renders the claim indefinite because there is no noun following the adjective “adjacent” which would indicate what the LNA moiety is adjacent to. As a result, the metes and bounds of the claimed structure are unclear. What is the LNA adjacent to? Is it adjacent to another LNA moiety, or is it potentially adjacent to other moieties, such as unmodified nucleotides?
Amending claim 7 to specify what the LNA moiety is adjacent to would obviate this rejection.
Claim 11 recites the term “said expression construct” in lines 3-4. There is insufficient antecedent basis for his term because claim 1, from which claim 11 depends, does not recite an expression construct.
Amending claim 11 to delete “or said expression construct” would obviate this rejection.
Claim Rejections - 35 USC § 102
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-3, 9 and 14-15 are rejected under 35 U.S.C. 102(a)(1)/102(a)(2) as being anticipated by WIPO Publication 2018/187624 to Feng (hereinafter ‘Feng’), as evidenced by Chen (Chen et al. LncRNA SNHG1 promotes α-synuclein aggregation and toxicity by targeting miR-15b-5p to activate SIAH1 in human neuroblastoma SH-SY5Y cells. NeuroToxicology, Volume 68, 2018, Pages 212-221.) and Yang (Yang et al. Sp1-Induced lncRNA Rmrp Promotes Mesangial Cell Proliferation and Fibrosis in Diabetic Nephropathy by Modulating the miR-1a-3p/JunD Pathway. Front. Endocrinol. 12:690784.).
Regarding claim 1, Feng teaches two lncRNAs, SNHG1 and RMRP, (a combination of nucleic acid agents) present in plasma (i.e., present in combination in the same composition), which are relevant as markers to distinguish healthy individuals from individuals with lung cancer (p. 48 ln 2-10). Chen and Yang evidence that the lncRNAs are capable of inhibiting miR-15b and miR-1a, respectively, as discussed in the rejection of the claim under 35 U.S.C. § 101.
Regarding claim 2, insofar as Feng teaches SNHG1 and RMRP in plasma, Feng also teaches wherein the combination of miR-15b and miR-1a, as evidenced by Chen and Yang and described above.
Regarding claim 3, Chen (see Fig. 4, which shows the interaction between SNHG1 and miR-15b-5p) and Yang (“Figure 4(F): Schematic illustration revealed the base complementation of miR-1a-3p with Rmrp”) evidence that the lncRNAs taught by Feng comprise a hybridizing sequence of nucleotides which is capable of forming a hybrid (binding) with the target microRNAs
Regarding claim 9, the broadest reasonable interpretation of the term “expression construct” encompasses
Regarding claims 14-15, the claims merely recite specific diseases relating to the intended use of the nucleic acid agents. As described in the rejection of the claims under 35 U.S.C. § 101, the recitation of an intended use in the preamble of the claim, when the body of the claim sets forth a structurally complete product, is not considered limiting.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
Determining the scope and contents of the prior art.
Ascertaining the differences between the prior art and the claims at issue.
Resolving the level of ordinary skill in the pertinent art.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-7 and 14-17 are rejected under 35 U.S.C. 103 as being unpatentable over Pan (Pan et al. miR-1 Exacerbates Cardiac Ischemia-Reperfusion Injury in Mouse Models. PLOS ONE 7(11): e50515.) in view of Hullinger (Hullinger et al. Inhibition of miR-15 Protects Against Cardiac Ischemic Injury. Circulation Research, Volume 110, Issue 1, 6 January 2012; Pages 71-81.).
A note on claim interpretation: While, as described in the rejections of the claims under 35 U.S.C. § 101, the recitation of the combination of nucleic acid agents “for use in treating heart disease” is not considered limiting, the use has been examined in the interests of customer service and compact prosecution.
Regarding claims 1 and 2, Pan teaches the use of a nucleic acid agent directed at and specifically inhibiting miR-1a to treat cardiac ischemia injury (heart disease) (Abstract):
LNA-antimiR-1 treatment significantly attenuated cardiac ischemia/reperfusion injury…this study demonstrated that miR-1 is a causal factor for cardiac injury and systemic LNA-antimiR-1 therapy is effective in ameliorating the problem.
Pan does not teach a combination of nucleic acid agents capable of inhibiting a combination of microRNAs, wherein the combination of microRNAs is miR-1a and miR-15b.
Hullinger teaches that, “…systemic delivery of a miR-15 anti-miR dose-dependently represses miR-15 family members in both murine and porcine cardiac tissue, whereas therapeutic dosing of anti-miR chemistries targeting miR-15 in mice reduces infarct size, inhibits cardiac remodeling, and enhances cardiac function in response to ischemic damage.” (p. 72).
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, absent objective evidence of nonobviousness such as unexpectedly superior results, to have combined the teachings of Pan and Hullinger by combining the miR-1a inhibitors to ameliorate cardiac injury, as taught by Pan, with the miR-15b inhibitors to ameliorate cardiac injury, as taught by Hullinger. The ordinary artisan would have been motivated to do and would have had a reasonable expectation of success based on the teachings of the prior art that each miRNA inhibitor was useful for the same purpose, and the idea of combining them flows logically from their having been taught individually in the prior art (MPEP 2144.06).
Regarding claim 3, both Pan and Hullinger teach that the miRNA inhibitors were antisense oligonucleotides (LNA-modified anti-miRs; see p. 72 and Figure 2 of Hullinger and p. 3 of Pan), i.e., nucleic acid agents comprising hybridizing sequences capable of forming a hybrid with the target miRNA.
Regarding claim 4: Pan teaches that, “the sequence of LNA antimiR-1 is 5’-ACTTCTTTACATTCC-3’”, which comprises SEQ ID NO: 001 (acttctttacattcc, underlined portion). Hullinger teaches that the antimir sequence for miR-15b is 5’-TGTAAACCATGATGTGCTGCT-3’ (Figure 2), which comprises SEQ ID NO: 002 (ccatgatgtgctgct, underlined portion).
Regarding claim 5, both Pan (p. 3) and Hullinger (Figure 2) teach that the nucleic acid agents comprise at least one LNA (see above).
Regarding claims 6 and 7, Hullinger teaches that the LNA-modified chemistries were fully phosphorothioated (Figure 2).
Regarding claims 14 and 15, both Pan and Hullinger teach wherein the heart disease is cardiac ischemic injury, and Hullinger teaches that ischemic heart disease is characterized by hypoxia of cardiomycytes/a result of myocardial infarction (p. 71):
Ischemic heart disease is induced by an insufficient oxygen supply to the myocardium, typically due to coronary artery disease or myocardial infarction. During an MI, occlusion of coronary vessels impedes a sufficient oxygen supply to the heart muscle and the resulting hypoxia results in loss of viable cardiac tissue”, i.e., characterized by hypoxia of cardiomyocytes
Regarding claims 16 and 17, both Pan and Hullinger teach the combination comprised in a pharmaceutical composition (i.e., a composition for in vivo administration; see Hullinger p. 76 and Pan p. 3).
Claims 8-11 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Pan and Hullinger as applied to claims 1-7 and 14-17, further in view of Lavenniah (Lavenniah et al. Engineered Circular RNA Sponges Act as miRNA Inhibitors to Attenuate Pressure Overload-Induced Cardiac Hypertrophy. Molecular Therapy, Volume 28, Issue 6, June 2020, Pages 1506-1517.).
Pan and Hullinger render obvious the combination of nucleic acid agents targeting a combination of miR-1a and miR-15b of claim 1, from which instantly the rejected claims depend, as described above.
Regarding claims 8-10 and 13, Pan and Hullinger do not teach wherein all of the nucleic acid agents are expressed intracellularly from a single exogenous expression construct under control of a cardiac Troponin T promoter operable in a human myocardial cell.
Lavenniah teaches a combination of nucleic acid agents capable of inhibiting miRNA (engineered circular RNA sponge “to target known cardiac pro-hypertrophic miR-132 and -212”, Abstract, with 6 binding sites each for miR-132 and miR-212, p. 1508).
Lavenniah further teaches the combination of nucleic acid agents expressed from AAV expression constructs under a cardiac troponin T promoter (p. 1510):
adeno-associated virus (AAV) serotype 9 vectors were employed to deliver and express constructs in vivo, specifically in cardiomyocytes (CMs), using the cardiac troponin T (cTnT) promoter.
Regarding claim 11, Lavenniah further teaches wherein the expression construct is encapsulated by a virus (see above).
Lavenniah provides a teaching, suggestion or motivation to substitute the LNA-modified antisense oligonucleotide constructs (antagomiRs) with a circular RNA sponge expression construct because, “circRNAs have the potential to sustain miRNA suppression for prolonged time periods and would in turn require minimal dosage, or longer dosing intervals, as compared to linear miRNA inhibitor administration” (p. 1508) and, “circmiRs exhibited improved efficacy compared to equimolar pharmacological antagomiRs in vitro and enhanced stability compared to linear counterparts” (Id.).
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 combination of nucleic acid agents as taught by Pan and Hullinger by expressing the anti-miRs from a circular RNA construct, as taught by Lavenniah. The ordinary artisan would have been motivated by Lavenniah’s teachings that circimiRs had the potential to sustain miRNA suppression for longer at minimal dosages, and would have had a reasonable expectation of success based on Lavenniah’s teachings that the circimiRs exhibited improved efficacy and stability compared to antagomiRs such as Pan and Hullinger’s antagomiRs.
Claims 11 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Pan and Hullinger as applied to claims 1-7 and 14-17, further in view of Zhi (Zhi et al. Effective Delivery of Hypertrophic miRNA Inhibitor by Cholesterol-Containing Nanocarriers for Preventing Pressure Overload Induced Cardiac Hypertrophy. Adv. Sci. 2019, 6, 1900023.).
Pan and Hullinger render obvious the combination of nucleic acid agents targeting a combination of miR-1a and miR-15b of claim 1, from which instantly the rejected claims depend, as described above.
Pan and Hullinger do not teach wherein the nucleic acid agents are bound to a nanoparticle, wherein the nanoparticle comprises a ligand facilitating delivery to or entry of the nanoparticle into a cardiomyocyte.
Zhi teaches miRNA inhibitors bound to nanoparticles, wherein the nanoparticles comprise a ligand facilitating delivery to cardiomyocytes (Abstract):
CHO-PGEA (cholesterol (CHO)-terminated ethanolamine-aminated poly(glycidyl methacrylate)) can efficiently condense small RNAs into nanosystems for preventing cardiac hypertrophy. CHO-PGEA contains two features: 1) lipophilic cholesterol groups enhance transfection efficiency in cardiomyocytes, 2) abundant hydrophilic hydroxyl groups benefit biocompatibility. miR-182, which is known to down regulate forkhead box O3, is selected as an intervention target and can be blocked by synthetic small RNA inhibitor of miR-182 (miR-182-in). CHO-PGEA can efficiently deliver miR-182-in into hearts. In the mice with aortic coarctation, CHO-PEGA/miR-182-in significantly suppresses cardiac hypertrophy without organ injury. This work demonstrates that CHO-PGEA/miRNA nanosystems are very promising for RNA-based therapeutics to treat heart diseases.
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 combination of nucleic acid agents (oligonucleotide miRNA inhibitors, a.k.a. antagomiRs) for use in treating ischemic cardiac injury by binding them to Zhi’s cholesterol-conjugated nanoparticles, to produce a composition suitable for delivering the antagomiRs to cardiomyocytes. The ordinary artisan would have had a reasonable expectation of success based on Zhi’s teachings that a similar oligonucleotide, a synthetic small RNA inhibitor of a miRNA, could successfully reach the heart and treat heart disease.
Claim Rejections - 35 USC § 112(a) – Enablement
Claims 1-17 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 a method of enhancing cardiac function and inducing cardiomyocyte proliferation after myocardial infarction, the method comprising administering a combination of the LNA-antagomirs of miR-1a and miR-15b listed on pages 26-27, or a combination of the LNA antagomirs of miR-1a, miR-15b and miR-27b, does not reasonably provide enablement for methods of a) preventing heart disease or b) treating all forms of heart disease using the full scope of all nucleic acid agents encompassed by claims 1-3 and 5-17. 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 test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the specification coupled with information known in the art without undue experimentation (United States v. Telectronics., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is needed is not based upon a single factor but rather is a conclusion reached by weighing many factors. These factors were outlined in Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter. 1986) and again in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988), and the most relevant factors are indicated below:
Nature of the Invention
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, 1330 (Fed. Cir. 2001).
Breadth of the Claims
Claim 1 recites the use of a combination of generic nucleic acid agent inhibitors of miR-1a in combination with miR-15b or in combination with miR-15b and miR-27b, for use in prevention and treatment of heart disease.
The broadest reasonable interpretation of the nucleic acid agents includes any kind of nucleic acid which can perform the claimed function of specifically inhibiting and/or degrading a target microRNA. These include various antisense, synthetic and naturally occurring non-coding nucleic acids such as linear antisense oligonucleotides (e.g., antagomiRs), circular RNA sponges, and long non-coding RNAs.
The broadest reasonable interpretation of heart disease encompasses a wide variety of diseases with a variety of underlying causes and symptoms. The Center for Cardiovascular Medicine at the Mayo Clinic lists several forms of heart disease, including congenital conditions (present at birth) such as atrial septal defects, Tetralogy of Fallot or transposition of the great arteries, and including conditions caused by viral or bacterial infection, such as myocarditis or rheumatic fever.
While the recitation of the intended use of the combination of nucleic acid agents in the preamble is not considered limiting, as described in the rejections of the claims under 35 U.S.C. 101, in the interests of customer service and compact prosecution, the intended use is being examined here. With that in mind, one of the intended uses of the invention is not only treatment but prevention. The instant specification provides examples of treatment, which encompasses ameliorating the disease or disorder, alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient, or modulating the disease or disorder (e.g., stabilization of a discernable symptom and/or physical parameter) (p. 6 ln 12-19). The instant specification does not clearly define or provide examples of prevention. However, the broadest reasonable interpretation of prevention encompasses both delaying the onset of a disease or disorder, including both discernible and indiscernible symptoms, or fully preventing any discernible or indiscernible symptom for an indefinite period of time.
Guidance of the Specification
The specification discloses that combination inhibition of miR-1a and miR-15b induces cardiomyocyte proliferation in vitro in 1- and 7-day-old rat cardiomyocytes (Example 2, p. 18-19), showing that 2 combinations (LNA-1a and LNA-15b; LNA-1a, LNA-15b and LNA-27b) had higher numbers of cardiomyocytes in telophase than other combinations. The inventors also showed that inhibition of miR-1a and miR-15b enhanced cardiac function after myocardial infarction in vivo (Example 3, p. 19-20), as well as enhancing cardiomyocyte proliferation (Example 4, p, 20-21). The instant specification further discloses similar results in human cardiomyocytes and human cardiac organoids in vitro (Examples 5-6 p. 21-22).
The specification does not disclose that the combination inhibition of those miRNAs treated other heart diseases such as congenital heart disease, viral myocarditis, hypercholesterolemia, etc. The specification also does not disclose that combination inhibition of those miRNAs prevented any disease or condition.
State of the Art
As described above, the art teaches that a wide variety of diseases and conditions falls under the umbrella of ‘heart disease’. These include conditions present at birth, such as Tetralogy of Fallot, and diseases often caused by infection, such as rheumatic fever or viral myocarditis. The ordinary artisan would not have had a reasonable expectation that combination inhibition of miR-1a/miR-15b/miR-27b would have successfully ameliorated a congenital heart condition, which is caused by structural defects present at birth, or a heart condition caused by infection.
Additionally, while the art shows that miR-1a inhibition consistently ameliorates ischemic cardiac injury after myocardial infarction, as discussed in the rejections of the claims under 35 U.S.C. 103, the art is more ambiguous regarding miR-1a’s role in other forms of heart disease. For example, Luo (Luo et al. Biochemical and Biophysical Research Communications, vol 495, no. 1, 5 November 2017, pages 607-613; of record, cited on an IDS) teaches that, in a rat model of heart failure induced by left ventricular pressure overload, restoration of miR-1a gene expression could reverse the pressure-induced cardiac hypertrophy (p. 608). In the context of cardiac development, the art shows that deletion (i.e., complete inhibition) of miR-1 “has profound consequences for development and maintenance of the heart. Mice lacking miR-1-2 have a spectrum of abnormalities, including VSDs in a subset that suffer early lethality, cardiac rhythm disturbances in those that survive, and a striking myocyte cell-cycle abnormality that leads to hyperplasia of the heart with nuclear division persisting postnatally” (Zhao et al. Dysregulation of Cardiogenesis, Cardiac Conduction, and Cell Cycle in Mice Lacking miRNA-1-2. Cell 129, 303–317, April 20, 2007.). This would indicate that inhibition of at least miR-1a during fetal development would not only not prevent or treat congenital heart disease, but may actually contribute to it.
The claims also explicitly encompass preventing heart disease. Looking to the prior art for guidance, a search of the prior art did not identify any methods which utilized the administration of miRNA or miRNA inhibitors which could effectively prevent heart disease in a subject, particularly in regards to congenital heart disease. In fact, no prior art was identified which taught effective prevention of heart disease using any agent similar to the agents utilized in the claims.
e. Experimentation Required
In order to practice the claimed invention, an undue amount of experimentation would be required. For example, it would be necessary for one of ordinary skill in the art to test the combination inhibition of the recited miRNAs for every heart disease or condition. and to further test the approach at all developmental stages for an indefinite period of time to determine whether the inhibition is fully preventative.
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 applicant and the specific examples, it is the conclusion that an undue amount experimentation would be required to make and use the invention as claimed.
Conclusion
No claim is allowed at this time.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMANDA M ZAHORIK whose telephone number is (703)756-1433. The examiner can normally be reached M-F 8:00-16:00 EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached on (571) 270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/AMANDA M ZAHORIK/Examiner, Art Unit 1636
Prosecution Insights