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 .
Claims 1-17 are pending and under examination.
This is the First Office Action on the Merits of US 18/039,187 filed on 05/26/2023 which is a 371 of PCT/US2021/062207 filed on 12/07/2021 which claims US priority benefit of US Provisional 63/122,789 filed on 12/08/2020. The Filing Receipt filed on 09/27/2023 is controlling.
Information Disclosure Statement
The IDS filed on 05/26/2023 has been considered by the examiner.
Claim Objections
Claim 1is objected to because of the following informalities:
Claim 1 has a typographical error in line. Amend as follows: a method for inhibiting or reducing the severity of proliferative vitreoretinopathy (PVR) [[is]] in a subject. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claims 4, and 15-17 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 4, and 15-17 each recite the limitation "the effective dose" in line 1. There is insufficient antecedent basis for this limitation in the claim because each of these claims depend from claim 1 which does not recite an effective dose. Claim 1 recites “in an amount sufficient to inhibit or reduce the severity of PVR but does not mention a dose effective to reduce epithelial-mesenchymal transformation of retinal epithelial cells (claim 4), to improve visual acuity (claim 15), to reduce risk of PVR reoccurrence (claim 16), or to improve likelihood of retinal reattachment following rhegmatogenous retinal detachment surgery (claim 17). The scope of claims 4, and 15-17 is unclear because it is unclear whether the amount sufficient to inhibit or reduce the severity of PVR in claim 1 is intended to be the same dose (the effective dose) recited in each of claims 4, and 15-17 which would be required to meet the specific limitations of claims 4, and 15-17.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(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.
Scope of 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 contacting Human adult retinal pigment epithelial cells (ARPE-19) with human GDF-15 protein comprising instant SEQ ID NO: 1, does not reasonably provide enablement for a method for inhibiting or reducing the severity of proliferative vitreoretinopathy (PVR) is a subject, by contacting retinal pigment epithelial cells in an eye of the subject with a composition GDF-15 in an amount sufficient to inhibit or reduce the severity of PVR. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use the invention commensurate in scope with these claims.
Many factors are to be considered when determining if sufficient evidence exists to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue". These factors include 1) the breadth of the claims, 2) the nature of the invention, 3) the state of the prior art, 4) the level of one of ordinary skill, 5) the level of predictability in the art, 6) the amount of direction provided by the inventor, 7) the existence of working examples, and 8) the quantity of experimentation needed to make or use the invention based on the content of the disclosure. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
The nature of the invention: The nature of the invention is inhibiting the severity of proliferative vitreoretinopathy (PVR) in a subject including a human subject. The nature of the invention is in the unpredictable biological arts.
The breadth of the claims: The claims are broad to inhibiting or reducing the severity of PVR in any subject including a human patient by contacting the eye with a GDF-15 which encompasses GDF-15 variants.
The state of the prior art: The state of the prior art is shown in Wischhusen et al entitled: Growth/Differentiation Factor-15 (GDF-15): From Biomarker to Novel Targetable Immune Checkpoint (Front Immunol published May 19 2020 11:951). Wischhusen et al disclose that GDF-15 is a divergent member of the transforming growth factor-β (TGF-β) superfamily. Wischhusen et al recites:
It contains seven conserved cysteine residues forming a cysteine knot that is the defining hallmark of the TGF-β superfamily. Among all superfamily members, orthologous GDF-15 molecules show the lowest sequence conservation across species. While mature rat, mouse and human TGF-β1 and BMP-2 proteins are 99–100% sequence identical between species, homology is below 70% for GDF-15. Moreover, promoter regions are entirely different between humans and mice.
Further, Idrees et al reviews the state of the art in “Proliferative Vitreoretinopathy: A Review” (Int Ophthalmol Clin 2019 Vol 59 No. 1: pages 221-240; IDS ref). Idrees et al disclose that PVR states that surgery is the only management option for PVR “as there is no proven pharmacologic agent for the treatment or prevention of PVR” but that “clinical trials of various agents to prevent PVR formation are ongoing” (see Abstract).
The predictability in the art: It is noted that generally the pharmaceutical art is unpredictable, requiring each embodiment to be individually assessed for physiological activity. In re Fisher, 427 F. 2d 833,166 USPQ18 (CCPA 1970). The instantly claimed invention is highly unpredictable because those of skill in the art recognize that in vitro assays and or cell-cultured based assays are generally useful to observe basic physiological and cellular phenomenon such as screening the effects of potential drugs. However, clinical correlations are generally lacking. For example, Verma et al discloses that a disadvantage of animal cell culture is that “this system cannot replace the complex live animal for testing the response of chemicals or the impact of vaccines or toxins”. (See Verma et al “Animal tissue culture principles and applications” Animal Biotechnology 2020 Jun 26:269–293; Page 281, left col.).
Further, the reference of Ilhan et al (“The Expression of GDF-15 in the Human Vitreous in the Presence of Retinal Pathologies with an Inflammatory Component”, Ocul Immunol Inflamm 2016 Vol 24 No.2, pages 178-183) shows unpredictability in the art of using GDF-15 for treating a human subject. For example, Ilhan et al discloses that GDF-15 protein is a multifunctional cytokine that has both pro-inflammatory and anti-inflammatory properties. (page 3, “Discussion”). Ilhan also does not specifically teach contacting retinal pigment epithelial cells in an eye of a subject with a composition comprising GDF-15 in an amount sufficient to inhibit or reduce the severity of PVR.
In addition, the art in the field of using GDF-15 in treating conditions in subjects including human patients suffering from PVR is shown to be unpredictable as evidenced by the reference of Kumar et al (US2019/0284257). Kumar et al disclose administering to a subject or patient antagonists of GDF-15. Antagonists include TBRII and antibodies directed against GDF-15.(pages 2-3). On page 67, Kumar et al disclose making purified human GDF15 to test binding affinities of TBRII to GDF15 (See page 67). Kumar et al discloses a method for treating different disorders including an inflammatory disorder and a retinal disease using members of the transforming growth factor-beta (TGFβ) superfamily (para [0002] - 'Members of the transforming growth factor-beta (TGFβ) superfamily are pleiotropic cytokines involved in essential cellular functions such as proliferation, differentiation, apoptosis, motility, extracellular matrix production, tissue remodeling, angiogenesis, immune response, cell adhesion, and also play a key role in pathophysiology of disease states as different as chronic inflammatory conditions'; para [0139] - 'polypeptide therapeutic agents of the disorders'), the inflammatory diabetes-related vascular include, disorders present disclosure are useful for treating or preventing method comprising administering an effective amount of selected TGFβ superfamily polypeptides including growth differentiation factor 15 (GDF15) (para [0026] - 'treating a disease or condition associated with a TGFβ superfamily member in a patient in need thereof, the method comprising administering to the patient an effective amount of the TβRII polypeptides the TGFβ superfamily member is GDF15'; para [0047] - Growth differentiation factor 15 (GDF15) is a member of the TGFβ family GDF15 has been described in the literature as macrophage inhibitory cytokine-1 (MIC-1), and non-steroidal anti-inflammatory activated gene-1 (NAG-1) reflecting the different functions that have been implied for this protein').
The presence or absence of working examples: The instant Specification states on page 1, para 0005, that there “is no current pharmacologic agent to treat or prevent PVR, presenting an unmet need”. The specification discloses an” exemplary amino acid sequence of human GDF-15 protein” is the instant SEQ ID NO: 1. (See para 0032.) The Specification provides one working example on pages 18-19 which teaches contacting ESC-NPC cells with GDF-15 but does not teach contacting or treating a subject. Example 1 results are shown in Figures 1-2. However, Example 1 is not a working Example of the claimed invention which requires contacting an eye, including an eye of a human patient, with a composition comprising GDF-15. Rather, the only working example provided in the Specification is drawn to a method of contacting ESC-NPC cells with GDF-15 (shown in Fig1B). Figure 2 shows culture of GDF-15 reduces TGFbeta-2-induced upregulation of phosph-Smad2 (A) and EMT marker Fibronectin (B) in ARPE-19 cells. Human adult retinal pigment epithelial cells (ARPE-19) were pre-treated with PBS or GDF-15 (50 ng/ml) for 1 h and then co-treated with PBS or TGFbeta-2 (1 ng/ml) for another hour (A) or 2 days (B) before harvest.
The amount of direction or guidance present: The guidance present in the specification is contacting ESC-NPC cells with GDF-15 but does not teach contacting or treating a subject. Example 1 results are shown in Figures 1-2.
The level of the skill in the art: The level of skill in the art is high, at the level of an MD or PhD research scientist.
The quantity of experimentation needed: The quantity of experimentation needed is undue. One skilled in the art would need to determine what diseases out of all known inflammatory diseases would be benefited by the mediation of miR-124 receptors and then would further need to determine which of the claimed compounds would provide treatment of the disease.
Thus, the specification fails to provide sufficient support of the use of the compounds of claim 1 for the inhibiting or reducing the severity of proliferative vitreoretinopathy.
Genentech Inc. v. Novo Nordisk A/S (CA FC) 42 USPQ2d 1001, states that "a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion" and "[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable".
Therefore, in view of the Wands factors and In re Fisher (CCPA 1970) discussed above, to practice the claimed invention herein, one of ordinary skill in the art would have to engage in undue experimentation to practice the full-scope of the claimed invention with no assurance of success.
Written Description
Claims 1-17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 1-17 are drawn to a method for inhibiting or reducing the severity of proliferative vitreoretinopathy in a subject by contacting retinal pigment epithelial cells in an eye of the subject with a composition comprising growth differentiation factor 15 in an amount sufficient to inhibit or reduce the severity of PVR.
Thus claims require the critically essential element of a composition comprising growth differentiation factor 15 in an amount sufficient to inhibit or reduce the severity of PVR in a subject. In addition, dependent claims 4, and 15-17 require a dose effective to reduce epithelial-mesenchymal transformation of retinal epithelial cells (claim 4), to improve visual acuity (claim 15), reduce risk of PVR reoccurrence (claim 16), or improve likelihood of retinal reattachment following rhegmatogenous retinal detachment surgery (claim 17). Claims are broad to any GDF15 except claim 11 which recites human GDF-15.
The fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, applicant was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc., 935 F.2d at 1563-64, 19 USPQ2d at 1117.
To satisfy the written description requirement, MPEP §2163 states, in part “...a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention.” Moreover, the written description requirement for a genus may be satisfied through sufficient description of a representative number of species by “...disclosure of relevant, identifying characteristics, 1.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between functional and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.”
The instant specification discloses that “Proliferative vitreoretinopathy (PVR) is a major complication of rhegmatogenous retinal detachment (RRD) where proliferative, contractile cellular membranes form in the vitreous and on both sides of the retina, resulting in tractional retinal detachment with fixed retinal folds” [para 0003]. The specification discloses that the development of PVR is a complex process and “may be intraretinal also, causing retinal shortening”. [para 004]. Further, treatment is “principally surgical and often requires multiple procedures, and many anatomically successful eyes do not recover good visual function”. [para 0003]. The instant specification shows a species of a GDF-15 protein being a 308 amino acid sequence which is human GDF-15 (see instant SEQ ID NO: 1). In paragraph 0034 the specification explicitly states that for therapeutic methods of the disclosure, “an individual may be treated with human GDF-15, or a biologically active fragment or variant thereof”. Thus the term GDF-15 in the claims is construed to include variants. In paragraph 0035, specific changes to the amino acid sequence of therapeutic human GDF-15 are contemplated. Working Example 1 (results shown in Figures 1-2) appear to show use of GDF-15 which is instant SEQ ID NO: 1 using ESC-derived NPCs in culture and in human adult retinal pigment epithelial cells (ARPE-19) in culture. No working examples in an animal model subject or with GDF-15 variants are shown. Therefore, present claims encompass a genus of therapeutic GDF-15 protein which includes amino acid variants of SEQ ID NO: 1 while still possessing specific functional properties for treating proliferative vitreoretinopathy in a human subject. (See instant specification para 0032).
However, the limited disclosure of the specification in view of the vast genus of GDF-15 variants encompassed by the claims does not adequately describe the entire genus of molecules encompassed by the claims.
Further, the state of the art does not show sufficient representative species of functional therapeutic GDF-15 variants so that one of ordinary skill in the art would be able to envision whether a given such species would be encompassed by the presently claimed invention. Specifically, the state of the art before the effective filing date of the presently claimed invention provides evidence that one of ordinary skill in the art would not be able to envision if a species of GDF-15 would possess the required complex functions of the present claims without performing trial and error experimentation. For example, Wischhusen et al entitled: Growth/Differentiation Factor-15 (GDF-15): From Biomarker to Novel Targetable Immune Checkpoint (Front Immunol published May 19 2020 11:951) disclose that GDF-15 is a divergent member of the transforming growth factor-β (TGF-β) superfamily. Wischhusen et al recites:
It contains seven conserved cysteine residues forming a cysteine knot that is the defining hallmark of the TGF-β superfamily. Among all superfamily members, orthologous GDF-15 molecules show the lowest sequence conservation across species. While mature rat, mouse and human TGF-β1 and BMP-2 proteins are 99–100% sequence identical between species, homology is below 70% for GDF-15. Moreover, promoter regions are entirely different between humans and mice.
Further, the prior art shows that amino acid changes alter the activity of a protein. For example, see Sengupta et al “Site-specific amino acid substitution in dodecameric peptides determines the stability and unfolding of c-MYC quadruplex promoting apoptosis in cancer cells”. (Nucleic Acids Research 2018, Vol 46, No 19, pages 9932-9950). Even post-filing art provides evidenced that even single amino acid changes to therapeutic proteins result in unpredictable properties of such proteins. For example, Forfar et al discloses that even a single amino acid sequence of a therapeutic protein may be critical to the function of the protein. See Forfar et al “Single Amino Acid Changes Impact the Ability of Drosophila melanogaster Cecropins to Inhibit Growth of Providencia Pathogens” (ACS Omega 2025 Vol 10 pages 5403-5414).
“Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features.” Ex parte Kubin, 83 USPQ2d 1410, 1417 (Bd. Pat. App. & Int. 2007) citing University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895. Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that the inventor(s) invented what is claimed.” (See Vas-Cath at page 1116).
Further, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eh Lily & Co., the court stated:
“A written description of an invention involving a chemical genus, like a description of a chemical species, ‘requires a precise definition, such as by structure, formula, [or] chemical name,’ of the claimed subject matter sufficient to distinguish it from other materials. Fiers, 984 F.2d at 1171, 25 USPQ2d at 1606; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284-85 (CCPA 1973) (‘In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus. ..."). Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The MPEP further states that if a biomolecule is described only by a functional characteristic, without any disclosed correlation between function and structure of the sequence, it is “not sufficient characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence.” MPEP 2163. The MPEP does state that for generic claim the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. MPEP 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP 2163. Although the MPEP does not define what constitute a sufficient number of representative, the Courts have indicated what do not constitute a representative number species to adequately describe a broad generic. In Gosteli, the Court determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gosteli, 872 F.2d at 1012, 10 USPQ2d at 1618.
In this case, the application does not identify any specific GDF-15 variants having the functional properties that are required of the instant claims..
The court and the Board have repeatedly held (Amgen Inc. v. Chugai Pharmaceutical Co. Ltd.,18 USPQ2d 1016 (CA FC, 1991); Fiers v. Revel, 25 USPQ2d 1601 (CA FC 1993); Fiddes v. Baird, 30 USPQ2d 1481 (BPAI 1993) and Regents of the Univ. Calif. v. Eh Lilly & Co., 43 USPQ2d 1398 (CA FC, 1997)) that an adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it, irrespective of the complexity or simplicity of the method; what is required is a description of the nucleic acid itself.
Thus, one of skill at the time of the invention could not have concluded that the inventor(s) were in possession of the genus of functional GDF-15 variants encompassed by the claims.
Conclusion
No claims are allowed.
Related prior art which may be applied in a future office action if appropriate:
Alford WO2021/207282 (with US priority to Prov 63/006680 filed on April 7, 2020) appears to be the closest prior art. Alford suggests a use of a secretome comprising a GDF-15 factor but does not disclose a method of inhibiting or reducing the severity of PVR in a subject by contacting retinal pigment epithelial cells in an eye of the subject with a composition comprising GDF-15 in an amount sufficient to inhibit or reduce the severity of PVR. The ‘680 Provisional (para 00341) recites: In some embodiments, the MSC secretome finds use in reducing neovascularization in the cornea. In some embodiments, the lyophilization and/or after being lyophilized (as well as reconstituted) MSC secretome finds use in the protection and repair of retinal epithelial cells and retinal ganglion cells. In some embodiments, the lyophilization and/or after being lyophilized (as well as reconstituted) MSC secretome finds use in induction of trabecular meshwork regeneration and reduction of intraocular pressure. Further, paragraph [0011] recites “In some embodiments, the MSC secretome for lyophilization and/or after being lyophilized further comprises at least one factor selected from the group consisting of Apolipoprotein A1, Complement Factor D, C-reactive protein, Cystatin C, DKK-1, Emmprin, Osteopontin, vitamin D BP, MIF, RANTES, uPAR, IL-17a, GDF-15, and/or IFNy.”
Ishikawa et al. (2015) "Resveratrol inhibits epithelial mesenchymal transition of retinal pigment A -epithelium and development of proliferative vitreoretinopathy. (Sci Rep. Vol. 5: 16386; IDS ref).
Klaassen et al. (2017) "Identification of proteins associated with clinical and pathological features of Proliferative diabetic retinopathy in vitreous and fibrovascular membranes". (PLOS One, 011e. 2017, 1.3 Vol. 12(11): e0187304; IDS ref)
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CATHERINE S. HIBBERT
Primary Examiner
Art Unit 1658
/CATHERINE S HIBBERT/Primary Examiner, Art Unit 1658