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 and Election
Claims 1-27 are pending.
Applicant’s election without traverse of the administered species “imatinib” in the reply filed June 3, 2026 is acknowledged. The elected species in the context of delivering to a patient with myxomatous mitral valve disease (MMVD) for the purpose of treatment appears to be free of the prior art. The search was widened to include other PDGFRB and PDGF antagonists and Prox1 coding sequences for gene therapy. Each of the searched species in the context of delivering to a patient with myxomatous mitral valve disease (MMVD) for the purpose of treatment also appears to be free of the prior art. Therefore, the species election requirement is withdrawn.
Claims 1-27 are under examination.
Drawings
The drawings are objected to because the lines, shadings, numbers and letters of FIGs 1B, 2A, 2C, 2D, 3G, 4D, 5C-H and 8E are not sufficient to provide satisfactory reproduction characteristics. 37 CFR 1.84(l) states that “all drawings must be made by a process which will give them satisfactory reproduction characteristics. Every line, number, and letter must be durable, clean, black (except for color drawings), sufficiently dense and dark, and uniformly thick and well-defined.” In the instant case, the text in the FIGs recited above is light grey or otherwise not sufficiently dense and dark to permit satisfactory reproduction characteristics and/or the text is very small and of poor resolution.
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 Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 3, 5-10, 12-14, 16, 18-23 and 25-26 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 1 and 14 recite “administering… a Prox1 mimic”. The metes and bounds of what a Prox1 mimic are undefined. The Specification does not give examples of any Prox1 mimic or explain what a Prox1 mimic is. It’s not clear if a Prox1 mimic is a nucleic acid, such as DNA or RNA, and if so how much of a coding sequence is required to be considered a Prox1 mimic. Alternatively, it is not clear if a Prox1 mimic is a protein or other non-nucleic acid molecule that is meant to mimic the function of Prox1. As such the claims are indefinite.
Claims 3, 5-10, 12-13, 16, 18-23 and 25-26 are rejected for depending from claims 1 or 14 and not remedying the indefiniteness.
It is noted that claims 2, 4, 11, 15, 17, 24 and 27 are not included in this rejection because they are interpreted to be limited PDGF or PDGFRB antagonists as the therapeutic agent in the composition.
Claim Rejections - 35 USC § 112(a)
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 1-27 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 treating MMVD with the PDGFR inhibitor imatinib, does not reasonably provide enablement for 1) treating MMVD with the genus of claimed agents including a Prox1 gene, or nucleic-acid based PDGF/RB antagonists or 2) preventing the suffering or symptoms of MMVD or preventing valve thickening. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
Exemplary factors to be considered in determining whether undue experimentation is required are summarized in In re Wands, 858 F.2d 731, 737, 8 U.S.P.Q.2d 1400, 1404 (Fed. Cir. 1988) (a) the breadth of the claims; (b) the nature of the invention; (c) the state of the prior art; (d) the level of one of ordinary skill; (e) the level of predictability in the art; (f) the amount of direction provided by the inventor; (g) the existence of working examples; and (h) the quantity of experimentation needed to make or use the invention based on the content of the disclosure. See MPEP 2164.01(a). All of these factors were considered, along with others, and a sufficient number are addressed below so as to create a prima facie case.
Claims 1 and 14 Analysis
Nature of the Invention and Breadth of Claims
Claims 1 and 14 are drawn to methods of MMVD treatment that also “prevents” thickening of heart valves, including MMVD characterized by mutations in Prox1 and/or upregulation of PDGF/RB-signaling. The specification does not define “treatment” or “treating”, which are interpreted to encompass the reduction and/or elimination of symptoms or severity of symptoms of a disease ([0028]). According to the Specification MMVD is characterized by thickening/softening valve leaflets with increased proteoglycans causing them to be billowed/loose/floppy which then leads to blood regurgitation back into the atria ([0008]-[0009]). Thus, treatment requires a reversal of the valve thickening and/or reduction of proteoglycan production in the mitral valves. Claims 1 and 14 also recites administering a therapeutic affective amount of a Prox1 gene, Prox1 mimic, a PDGF antagonist or a PDGFRB antagonist, which encompasses a large genus of diverse agents, including gene therapies, RNAi therapies, antibodies, and small molecules. Accordingly, enablement of the method requires one skilled in the art to deliver the genus of agents including gene therapy, small molecules, antibodies, RNAi agents to mitral valves, and in the case of gene therapy or RNAi agents, gain access to the appropriate cells to function. For the reasons provided below, Applicant have not sufficiently disclosed methods and protocols that would enable the skilled artisan to practice the invention commensurate in scope with these claims.
Guidance in the Specification
The specification elegantly demonstrates that the absence of Prox1 signaling in valvular endothelial cells (VECs) leads to increased thickness in mitral and aortic valves, cusp separation and fractional valve opening ([0060]). Loss of Prox1 also leads to abnormal extracellular matrix (ECM) composition which is a defining characteristic of valve disease ([0062]). Applicant also demonstrate that loss of Prox1 causes increased PDGF-B signaling ([0070]), which then increases expression of proteoglycans ([0082]-[0083]) which is implicated in MMVD ([0008]). Applicant also shows that PDGFB levels are increased in MMVD patients ([0088]). Finally, Applicant administers an FDA-approved monoclonal antibody imatinib, which inhibits the activity of receptor tyrosine kinases including the receptors for PDGFA and PDGFB, c-Kit and BCR-ABL ([0092]). Imatinib did not reduce the thickness of the mitral valves, although it did normalize elastin expression ([0092]).
In summary, Applicants were able to demonstrate that a single therapeutic agent, the non-specific PDGFRB antagonist imatinib, could reduce a single symptom of MMVD – increased elastin expression – that is caused by the lack of Prox1 expression. Applicant did not attempt to rescue Prox1-/- mice by delivering gene therapy agents encoding Prox1 or attempt to reduce expression of PDGFB or PDGFRB by using RNAi agents or small molecules. Additionally, from Applicant’s data it does not appear that providing imatinib or any other “therapeutic agent” is capable of preventing symptom onset of MMVD. Thus, in view of the Specification it was unpredictable whether replacing Prox1 expression or inhibiting PDGF[R]B expression in mitral valves is (1) even possible and (2) effective at treating MMVD.
State of the Prior Art
Tang reviews the state of understanding about myxomatous mitral valve disease (MMVD) around the effective filing date of the claimed invention (Tang et al., Frontiers in Cardiovascular Medicine (2022), 9:872288). MMVD and Mitral Valve Prolapse (MVP), as it is more commonly called in humans (page 2, ¶1), is characterized by leaflet thickening and deformity, increased expression of proteolytic enzymes, disorganized ECM, and increased number of valve interstitial cells (VICs) (page 2, ¶2). Mitral leaflets have 3 (or 4) layers with an inner spongiosa layer a bottom collagen-rich fibrosa layer, and lined with valve endothelial cells (VECs) (page 2, last ¶; FIG 1). MMVD is characterized by loss of endothelial cells and expansion of the inner layer of spongiosa, loss of mature collagen, and accumulation of ECM rich in glycosaminoglycans (GAGs), such as hyaluronan, and various proteoglycans (page 3, ¶2; FIG 1). Thus, treatment of MMVD should include increases in VECs, a reduction in proteoglycans and the spongiosa, and reestablishment of the fibrotic layer. Tang focuses on the role of TGFb-signaling in MVP/MMVD and suggests that increased TGFb-signaling promotes VEC transitions to mesenchymal cells, increases peptidoglycan production, and promotes overall myxomatous degeneration (Fig 3). Importantly, Tang concludes that “further understanding [of] the molecular mechanisms of MMVD is needed to identify pharmacological manipulation strategies of the signaling pathway… and so control the disease onset and development” (Abstract). Thus, Tang teaches that around the effective filing date of the claimed invention, there was no pharmacological treatments of MMVD. This finding is corroborated by Harky who summarizes current interventions for mitral valve disease and only discloses surgical and prosthetic interventions (Harky et al., Progress in Cardiovascular Diseases (2021), 67: 98-104). Thus, it was completely unpredictable what type of pharmacological compositions could even be used to abrogate or modify the signaling and gene expression pathways in mitral valves.
Gene therapy has been proposed as a therapeutic intervention by Applicants (i.e., Prox1 gene, RNA, DNA, shRNA, siRNA) ([0027], [0029]). However, as of the effective filing date of the claimed invention, there is no evidence of delivering therapeutic nucleic acids specifically to heart valves for therapeutic intervention. All previous attempts at delivering nucleic acids to valvular cells were performed in cells isolated form aortic or cardiac valves (i.e., ex vivo). See e.g., Voicu et al., Int. J. Mol. Sci. (2022), 23: 3824; Gee et al., Arterioscler Thromb Vasc Biol. (2020), 40:638–655. A review by Nappi and colleagues in 2021 discussed the role of miRNA in valvular heart diseases, including their possible role as therapeutic targets (Nappi et al., Int. J. Mol. Sci. (2021), 22: 12132). Nappi states in their concluding remarks “At present, no clinical data on therapeutic approaches targeting miRNAs are available and hypotheses formulation for future miRNAs practical use remains difficult.” (Section 5, ¶3). Therefore, it was unknown how to target therapeutic nucleic acids to mitral valve cells or which cells to target given the changing populations of cells during valve degeneration.
Thus, in view of the prior art, it would be highly unpredictable whether replacing Prox1 expression or inhibiting PDGF[R]B expression in mitral valves is (1) even possible and (2) effective at treating MMVD. Additionally, given the complex paracrine signaling in valvular tissue, the effect of using non-specific paracrine signaling inhibitors was also unpredictable.
Experimentation Required
In order to practice the invention, one skilled in the art would need to determine means to deliver therapeutic nucleic acids to mitral valve cells, including VEC-specific viral and non-viral vectors. Applicants would also need to determine the correct expression level for Prox1 gene and/or PDGF[R]beta inhibitory RNAs. Given that no means to specifically target therapeutic nucleic acids to mitral valve cells currently exists, the development of such would constitute its own separate invention, which the skilled artisan would conclude is undue. Additionally, the skilled artisan would need to determine the effectiveness and dosage amounts for the plethora of possible PDGF[R]beta antagonists and modes for targeting specifically mitral valvular cells. Given that many of the recited antagonists are not specific for PDGF[R] beta, and the intricate signaling pathways involved in MMVD as taught in Tang, determining which inhibitors have a therapeutic effect and at which doses, constitutes ~ 50 individual clinical trials, which the skilled artisan would also conclude is undue.
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 lack of working examples of using Prox1 genes or mimics, inhibitor nucleic acids, and most of the recited PDGF[R]B inhibitors, it is the conclusion that an undue experimentation would be required to make and use the invention.
Dependent claims
Claims 3, 5-13, 16 and 18-26 do not limit the therapeutic agent and are rejected for the reasons recited above for claims 1 and 14.
Claims 2 and 15 limit the therapeutic agent to approximately 50 “PDGF or PDGFRB antagonists”. Each of the recited antagonists are known to target PDGF and/or PDGFRB along with other proteins, including many receptor tyrosine kinases. For instance, SU 4312 is VEGF inhibitor and a weak PDGF inhibitor. Given the complexity of paracrine signaling in valvular tissues, including TGF beta, BMP, and the disclosed PDGF signaling, it is unknown how non-specific PDGF antagonists would affect MMVD and possible valvular regeneration. In Applicant’s own working example, treatment with imatinib was unsuccessful at ameliorating the progressive valve thickening upon Prox1 deletion ([0092]). Applicant concluded that imatinib “partially rescued” valve defects. It is interesting to note that imatinib can also target TGF beta, whose expression is known to be upregulated in MMVD. Thus, it is possible that the partial rescue by imatinib documented by Applicant is acting through TGF beta pathways and not PDGF-beta pathways. Given the complexity of paracrine signaling in the mitral valve tissues and the non-specificity of the recited antagonists, the skilled artisan could not reasonably predict which of the antagonists would treat MMVD.
Claims 4, 11, 17 and 24 are limited to using imatinib as the therapeutic agent. However, the claims depend from claims 1 and 14 which recite “prevents thickening of heart valves and delays onset of clinical symptoms.” Applicant only demonstrates administering imatinib to mice that already have degenerated mitral valves caused by a reduction in Prox1 expression. Although Applicant concludes that imatinib “partially rescued the valve defects” by normalizing elastin levels, imatinib could not reduce valve thickening. Thus, it was unpredictable whether imatinib could prevent valve thickening in the first place.
Claim 27 is limited to methods using generic PDGF and PDGFR antagonists and are not fully enabled for the reasons outlined above for claims 2 and 15. Additionally, claim 27 recites “preventing the suffering from MMVD in a human patient”. The Specification completely lacks working examples for how to prevent MMVD before it develops. Each of the experiments used Prox1 deletion in VECs from birth. Additionally, the only therapeutic example using imatinib had no effect on valve thickness. Thus, it was completely unpredictable that even imatinib could prevent thickening of heart valves when there was a genetic cause of MMVD.
Relevant Prior Art
Kauth reports the administration of imatinib to a patient with chronic eosinophilic leukemia, which improved mitral regurgitation (Krauth et al., Leukemia Research (2008), 32: 1779-1783). Kauth does not assay mitral valve thickness, so it is not clear if imatinib reduced valve thickness or if the mitral regurgitation was caused by MMVD.
Leong reports the long-term administration of imatinib to dogs diagnosed with pulmonary hypertension secondary to chronic degenerative mitral valve disease (CDMVD) (Leong et al., Thai J. Vet. Med. (2018), 48: 499-505). It appears from the literature that CDMVD is synonymous with MMVD. However, Leong did not disclose the thickness or overall anatomy of the heart valves. So, while Leong teaches treating MMVD with imatinib, it is not known whether imatinib treatment “prevents thickening of heart valves” as claimed.
Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CATHERINE KONOPKA whose telephone number is (571)272-0330. The examiner can normally be reached Mon - Fri 7- 4.
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/CATHERINE KONOPKA/Primary Examiner, Art Unit 1635
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