DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of Group II, claims 10-12, 14, 15, 19-21, 26, 27, in the reply filed on 3/12/26 is acknowledged.
Claims 1-3, 5, 7, 8, 28, 32, 33, and 35 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 3/12/26.
Applicant’s election without traverse of the SPECIES SEQ ID NO:11 in the reply filed on 3/12/26 is acknowledged.
Claims 19-21 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election of species was made without traverse in the reply filed on 3/12/26.
The polypeptide corresponding to SEQ ID NO:11 was searched and found to be human progranulin, also identified as human epithelin precursor and human proepithelin protein.
The examiner notes that the rejections below extend beyond the elected species for compact prosecution, and also that the bases of some of the rejections are relevant to applicant to consider for withdrawn claims 19-21, which are properly withdrawn based on species election.
Claim Status
Claims 1-3, 5, 7, 8, 10-12, 14, 15, 19-21, 26-28, 32, 33, 35 are pending.
Claims 4, 6, 9, 13, 16-18, 22-25, 29-31, 34 are cancelled.
Claims 1-3, 5, 7, 8, 28, 32, 33, and 35, are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 3/12/26.
Claims 19-21 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election of species was made without traverse in the reply filed on 3/12/26.
Claims 10-12, 14, 15, 26, 27 are pending and under examination.
Claims 10-12, 14, 15, 26, 27 are rejected.
Priority
The instant application, filed 07/26/2023 is a National Stage entry of PCT/US22/14019 , International Filing Date: 01/27/2022
PCT/US22/14019 Claims Priority from Provisional Application 63142156 , filed 01/27/2021
PCT/US22/14019 Claims Priority from Provisional Application 63163234 , filed 03/19/2021
Information Disclosure Statement
The Examiner has considered the reference(s) provided in the 1/8/24 Information Disclosure Statement, and provides a signed and dated copy of such herewith.
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Specification
The disclosure is objected to because of the following informalities: on page 31, para 132, line 4, reference is made to Table S1. The examiner does not find a Table S1 in the application as filed. It appears that applicant intended to refer to what is Table 2 in the instant application (vs. a scientific journal article).
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 10-12, 14, 15, 26, 27 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
As stated in MPEP 2164.01, “Any analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention. The standard for determining whether the specification meets the enablement requirement was cast in the Supreme Court decision of Mineral Separation v. Hyde, 242 U.S. 261, 270 (1916) which postured the question: is the experimentation needed to practice the invention undue or unreasonable? That standard is still the one to be applied. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). Accordingly, even though the statute does not use the term “undue experimentation,” it has been interpreted to require that the claimed invention be enabled so that any person skilled in the art can make and use the invention without undue experimentation. In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404 (Fed. Cir. 1988).”
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)” (emphasis added).
Pursuant to In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), one considers the following factors to determine whether undue experimentation is required (also recited in MPEP 2164.01(a)): (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. Some experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
The analysis of these factors is as follows:
(A) The breadth of the claims: broad as to what is being administered based at least on paras 86-88 of the specification, which encompass granulin or ZBTB7B polypeptides that may have 100% sequence identity with a natural protein, or, alternatively, any number of additions, deletions, or conservative substitutions of one or more amino acids of the peptide, “yet still retain functionality as described herein,” this without providing the structure/function relationship(s) required to retain such functionality. Sequence identity to identified proteins can be as low as 70%. What applicant sets forth is a large genus of possible polypeptides, including fusion forms, para 88, with a functionality requirement that lacks guidance as to what is needed to retain functionality. As to the administering step and objective of the claim 10 method, a polypeptide of such genus is administered to a patient’s eye “in an amount effective to reduce corneal fibrosis in the patient.”
(B) The nature of the invention: therapeutic, to reduce corneal fibrosis in the patient regardless of the cause of the corneal fibrosis.
(C) The state of the prior art:
Liu et al., PLOS ONE March 2014 vol. 9, issue 3, e92743, teaches that Atsttrin, a progranulin (PGRN)-derived molecule composed of three TNFR-binding domains of PGRN, binds to TNF receptors (TNFR) and is therapeutic against inflammatory arthritis, Abstract. The first para of the Introduction states, “Progranulin (PGRN) is a growth factor with multiple biological functions including anti-inflammation and immune regulations [1]. PGRN contains seven-and-a-half repeats of a cysteine-rich motif (CX5–6CX5CCX8CCX6CCXDX2HCCPX4CX5–6C) in the order P-G-F-B-A-C-D-E, where A-G are full repeats and P is the half-motif [2]. PGRN was reported to bind to TNF receptors (TNFR) through three individual and separate binding domains involving granulin A, C and F plus adjacent linkers [3]. Atsttrin (Antagonist of TNF/TNFR Signaling via Targeting to TNF Receptors) is an engineered molecule composed of half units of granulins A, C and F plus linkers P3, P4 and P5 that appears to be the ‘‘minimal’’ engineered molecule retaining affinity to TNFR [3–5]. Atsttrin was reported to selectively bind to TNFR and inhibited the binding of TNFa to TNFR in vitro. In addition, recombinant Atsttrin protein effectively attenuated inflammation in several animal models, including collagen antibody- and collagen-induced arthritis models, TNF transgenic mice and dermatitis model [3,6], indicating that Atsttrin may represent a novel biologics for treating various kinds of TNF/TNFR associated inflammatory diseases and conditions [3–5,7].” This reference further expands the knowledge base by reporting that the discovery of TNFRSF25 (DR3) as an additional Atsttrin-interacting member in TNFR family.”
Wang et al., Protein Cell 2015, 6(11):792–803, reviews the evolution of research regarding progranulin/TNFR interactions, see Table 1, page 796 and associated text, revealing complicated interactions in multiple models/tissues/cells, and on page 799 states that “PGRN is an important endogenous anti-inflammatory molecule that binds to three members in TNFR subfamily, i.e. TNFR1, TNFR2, and DR3. PGRN and its derived Atsttrin appear to exert their anti-inflammatory activities 1) by activation of PGRN/TNFR2 protective pathway through acting as a new ligand of TNFR2, which is known to mediate beneficial and protective roles in joint destruction and inflammatory processes (Aggarwal, 2014; Bluml et al., 2010; Bluml et al., 2012; Faustman and Davis, 2010; McCann et al., 2014), and 2) by inhibition of TNF/TNFR1 and TL1A/DR3 inflammatory signaling through functioning as the antagonist of TNF-α and TL1A (See proposed model in Fig. 5),” underline emphasis added.
In contrast to the above-stated anti-inflammatory roles and prospects of progranulin and also its shortened-form derivative Atsttrin, Siaka et al, American Journal of Pathology, Vol. 168, No. 6, June 2006, pp 1848-1860, evaluates effects of knocking out TNFalpha (TNFalpha null), this resulting in excessive invasion of macrophages in an alkali-burned cornea in a mouse model, and subsequent formation of a vascularized scar tissue, Abstract, pages 1848-1849. “The results show that loss of TNFα potentiates undesirable actions of transforming growth factor β (TGFβ) or activin/Smad in the tissue repair process, resulting in severe and persistent inflammation, fibrosis and neovascularization.”
Based on the teachings from Siaka, the Wang-stated second role of PGRN and Atsttrin could result in increased corneal fibrosis rather than a reduction of corneal fibrosis. The particular polypeptide, the timing and amount of its administering, as well as other factors – including the cause of the corneal fibrosis that is envisioned to be treated (rather than exacerbated), may be critical in achieving a desired treatment result given the complex and subtle signaling involved in the wound healing in the cornea, which as Wilson, Exp Eye Res. 2020 December ; 201: 108272. doi:10.1016/j.exer.2020.108272, teaches, utilizes complex interactions involving myofibroblasts from different lineages, and involves differing response times for healing different corneal injuries, such subtlety and complexity also supported by McKay et al., Eye (2020) 34:271–278, and Menko et al., THE ANATOMICAL RECORD 303:1689–1702 (2020).
(D) The level of one of ordinary skill: moderate to highly skilled, at least with a college degree in chemistry, biology, pharmacology or similar education.
(E) The level of predictability in the art: not high given the teachings of the prior art references.
(F) The amount of direction provided by the inventor: broad direction as to range of polypeptides that could be administered, with no guidance as to how to choose a polypeptide that retains a or multiple desired and needed functions.
(G) The existence of working examples: there is no data for the claimed method, actually administering an agent per claim 10 to treat corneal fibrosis. This includes that there is no data for administering the elected SEQ ID NO:11 polypeptide to treat corneal fibrosis, so this rejection, particularly (C) The state of the prior art, above, weighs against the full protein of progranulin being effective to treat corneal fibrosis without evidence of such (this also involves determining an effective amount). Data taken from other studies to analyze significance of GRN and ZBTB7B is noted, however these are from studies involving different tissues – lungs and trachea, cell culture studies – human keratocytes conversion to myofibroblasts reversed by ethyl pyruvate, and different types of damage to cornea, e.g., silver nitrate to rabbit eye corneas. These were used inter alia to demonstrate changes in gene expression to support a role in CCO causation, however what is claimed is broader, to treat fibrosis (i.e., from any cause of fibrosis) in a patient (not just a patient having congenital corneal opacities, CCO).
That work is still to be conducted to enable the invention is suggested at page 38, para 149, “We can explore structure-wound-healing activity of the modules GRN1-GRN7, and use (or manipulate) one or combination of these in identifying the most effective in wound-healing of corneal scars to achieve transparency.”
and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure:
Based on the above, weighing heavily on 1) the potential breadth and diversity of the genus of polypeptides that could be administered if functionality were identified, this itself involving much experimentation, 2) the complexity of pathways involved in wound healing and fibrosis and potential contradictory effects of progranulin-type polypeptides in their effect(s) on TNFalpha such that such effect(s) potentiate undesirable actions of transforming growth factor β (TGFβ) or activin/Smad in the tissue repair process, resulting in severe and persistent inflammation, fibrosis and neovascularization of the cornea, 3) the cornea itself a very special tissue the function of which requires transparency, so would be expected to have particularly exacting balancing of pathways, so requiring additionally very sensitive dosing of any agent administered toward effectuating an improvement, and given the lack of relevant examples commensurate with the scope of what is claimed, the examiner concludes that undue experimentation would be required to enable the invention as claimed, and therefore the claims under examination, claims 10-12, 14, 15, 26, 27, are rejected based on a clear lack of enablement.
Claims 10-12, 14, 15, 26, 27 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.
This rejection extends beyond the elected species for compact prosecution.
The claimed subject matter is not supported by an adequate written description. There are insufficient guidance, structure/function relationships such as correlations between a particular structure and a function, and/or other relevant disclosure, nor examples that are representative of the diversity of the genera encompassed by the claim 10 granulin polypeptide and the claim 10 ZBTB7B polypeptide.
The skilled artisan cannot envision the detailed chemical structure alternatives (i.e., amino acid sequences) of the encompassed polypeptides which have the respective required activity/function without further testing, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of identification. Adequate written description requires more than a mere statement that it is part of the invention. The compound itself is required; in this case at least a sufficient number of species that are representative of the diversity of each respective genus, and/or a disclosure of what is critical as far as sequence(s) and what does not work to achieve a particular claimed activity/function. Here, given the breadth of possible modifications which nonetheless require that the polypeptide retains the required biological activity of the original polypeptide sequence, the skilled artisan is left to determine what range of variations can still provide some level of relevant biological activity. This is leaving completion of the invention to someone else. See also Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991). One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483 (BPAI 1993). In Fiddes, claims directed to mammalian FGF's were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
In the instant case, the possibly broad and diverse genus of polypeptides that are to be administered are for the skilled artisan, rather than the instant applicants, to determine, including as to what range of variations can still provide some level of relevant biological activity to achieve the claimed treating of corneal fibrosis in a range of patients having a range of injuries or conditions causing the fibrosis.
Therefore, the full breadth of the claims does not meet the written description provision of 35 U.S.C. §112, first paragraph. Applicants are reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115).
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 15 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. The method of claim 1, from which claim 15 depends via claim 11, requires administering a granulin and/or a ZBTB7B POLYPEPTIDE, whereas what ‘is administered’ (passively) in claim 15 is a nucleic acid. Notwithstanding that such nucleic acid comprises a gene for expressing the granulin polypeptide in the patient’s eye, claim 15 impermissibly extends beyond the scope of what claim 10 claims, administering a polypeptide. Administering a nucleic acid is NOT a further limitation of administering a polypeptide. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 26 and 27 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.
Claim 26 includes the phrasing “administering both of a granulin polypeptide and/or a ZBTB7B polypeptide”. ‘Both’ followed by ‘and/or’ is confusing – are both required, or only one of the granulin polypeptide and the ZBTB7B polypeptide? This is not clear.
Claim 27 includes the phrasing “both administering a granulin polypeptide and/or a ZBTB7B polypeptide”. ‘Both’ followed by ‘and/or’ is confusing – are both required, or only one of the granulin polypeptide and the ZBTB7B polypeptide, OR is the both related to the “knocking down” limitation? This is not clear. The rejection of claim 26 can be overcome by amending to delete “both” if what is intended is to administer one or both of the granulin polypeptide and the ZBTB7B polypeptide, AND also per the claim knocking down expression as set forth in the last two lines of the claim.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOSEPH FISCHER whose telephone number is (571)270-7925, and whose direct facsimile number is (571)270-8925. The examiner can normally be reached on Monday to Friday, 9:00 AM to 5:00 PM, however noting that the examiner will not normally be working on Monday/Tuesday and on Wednesday-Friday on alternating weeks, but will promptly answer messages upon his return to work.
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/JOSEPH FISCHER/Primary Examiner, Art Unit 1658