DETAILED ACTION
Notice of Pre-AIA or AIA Status
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Election/Restrictions
Applicant’s election without traverse of group I (peptide prodrugs) and the compound of claim 75 in the reply filed on 26 May, 2026 and the phone call with Rick Shoop, applicant’s representative, on 8 June, 2026 is acknowledged.
The requirement is deemed proper and is therefore made FINAL.
Applicants have elected the compound of claim 75. A search was conducted for this invention, and references rendering it obvious were found. As a result, claims 43, 48, and 75-77 were examined and claims 49-53 and 78-95 have been withdrawn from consideration.
Claims Status
Claims 43, 48-53, and 75-95 are pending.
Claims 43, 48, and 50-53 have been amended.
Claims 75-79 are new.
Claims 49-53 and 78-95 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.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 was made without traverse in the reply filed on 26 May and 8 June, 2026.
Information Disclosure Statement
The information disclosure statement filed 2 July, 2025 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. The application data file had three references which were not clearly the same as the citations in the information disclosure statement. One of the references was illegible. Thus, they were not considered.
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.
first rejection
Claims 43 and 49 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 43, and claims dependent on it, describes a structure EY005-R, which is a tetrapeptide with an R group attached directly to the C-terminus by an ester bond. However, the claim also states that the R group can be attached to the C-terminus through a linker, which is not in the structure. In other words, the claims state that there is no linker (in the structure) and that there can be a linker (in the text), which is contradictory.
second rejection
Claims 76 and 77 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 76 and 77 require that the ester bond be cleaved under different conditions, but the tests are poorly defined. For example, claim 76 requires that carboxyesterases in the eye can cleave the ester bond. At pH 12 with PPT concentrations of the enzyme, for 30 seconds, it is not likely to have significant cleavage, even if under a different set of conditions the construct will cleave. Similarly, claim 77 requires “physiological conditions.” That can be in the gastric acid of the stomach or immured in a lipid bilayer. Nor is it clear if this test is conducted without the everpresent esterases found in tissue.
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:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 43, 48, and 75-77 are rejected under 35 U.S.C. 103 as being unpatentable over Pang et al (Med. Hypothesis Discov. Imnov. Ophthalmol. (2015) 4(3) p120-126) in view of Barot et al (Med. Chem. (2012) 8(4) p753-768), Larsen et al (Eur. J. Pharmaceut. Sci. (2004) 22 p399-408) and Kabanov et al (Prot. Eng. (1989) 3(1) p39-42).
Pang et al teach that facet of glaucoma is optic nerve head cupping and visual field defects caused by apoptosis of retinal ganglion cells (RGC) (p120, 1st column, 1st paragraph), and that lowering the pressure, the standard therapy for the disorder, by itself, cannot prevent progressive loss of visual field (p120, 2nd column, 1st paragraph). At least part of this is due to mitochondrial dysfunction (p121, 1st column, 1st paragraph). A pharmacological agent that ameliorates oxidative stress and enhances RGCs mitochondrial function should be able to reduce the rate of visual field loss in glaucoma (p122, 1st column, 3d paragraph). SS-31 is suggested as an agent that will be successful in this role (p122, 2nd column, 1st paragraph). Note that this is the same sequence as applicant’s elected species, save for the C-terminal modification (compare fig 1, 122, 2nd column, bottom of page with applicant’s elected species). In a different optical disorder, the peptide was shown to protect RGCs (p123, 2nd column, 2nd paragraph).
The difference between this reference and the examined claims is that this reference does not discuss an ester bond to a fatty alcohol (or other moiety).
Barot et al discuss prodrug strategies for ocular delivery (title). Topical administration is favored due to localized drug activity (1st page, 1st paragraph). However, poor penetration is a major restriction of this route of administration, which can be helped with a prodrug approach (1st page, 1st paragraph). This can improve passage through biological barriers (2nd page, 1st paragraph). The prodrug is preferably soluble (for administration as eyedrops) but possess optimal lipophilicity to diffuse across optical barriers (2nd page, 2nd paragraph). Ester prodrugs are the most common ophthalmic prodrug strategy (3d page, 2nd paragraph), which can greatly increase corneal penetration compared to unmodified drugs (3d page, 3d paragraph). Enzyme catalyzed hydrolysis is dependent on the ester, with unhindered straight chain aliphatic esters most rapidly hydrolyzed, compared to more sterically hindered esters (3d page, 4th paragraph). The hydrolysis of the ester bond can lead to low levels of the prodrug in the eye, which drives diffusion across the cornea (4th page, 1st paragraph). Note that varying the prodrug moiety can yield relatively large differences in hydrophobicity and permeation (4th page, 1st and 2nd paragraphs). Lipid prodrug moieties readily diffuse across the cornea, but, if too lipophilic, can be trapped there, showing that there is an optimal lipophilicity for transport (9th page, 2nd and 3d paragraphs). This reference discusses attachments of fatty alcohols to carboxylate drugs to allow for topical administration of optical drugs to cross the corneal barrier.
Larsen et al discuss ester prodrugs to increase hydrophobicity of peptides for oil based depot formulations (abstract). While for a different purpose, this is the same principle as that described in Barot et al; esterification of a carboxylate with a fatty alcohol to increase lipophilicity, which can be cleaved off in vivo. The structure used a model peptide, Gly-Phe, with fatty alcohols of various lengths attached via an ester linkage to the C-terminus (fig 1, p401, 1st column, top of page). The rate of hydrolysis of the ester (not enzyme catalyzed) was inversely related to the length of the fatty alcohol (fig 4, p405, 1st column, bottom of page). While considerably enhanced, the same pattern was seen in human plasma (table 1, p406, 1st column, top of page), which is attributed to esterase cleavage (p406, 1st column, 2nd paragraph). This reference discusses ester prodrugs of peptides, using the C-terminal carboxylate as the binding site.
Kabanov et al discuss lipid modification of proteins for membrane transport (title). This modification can be used to allow proteins to pass through the blood brain barrier, and the cell membrane (abstract). In other words, it is a general approach to endowing proteins with generic membrane permeability. The lipid modification uses stearoyl chloride (p39, 2nd column, 2nd paragraph, fig 2, p40, 1st column, middle of page, fig 3, p40, 2nd column, top of page, for example). This reference shows that relatively long lipid chains (C18, stearoyl) can be used to lipidate polypeptides for membrane transport.
Therefore, it would be obvious to lipidate the peptide of Pang et al, to allow for topical administration, as described by Barot et al, as a preferred administration route. As Barot et al describes a number of examples, an artisan in this field would attempt this modification with a reasonable expectation of success.
Furthermore, it would be obvious to attach the lipid as an ester to the C-terminus of the peptide of Pang et al as Larsen et al show this is a strategy that can be used for peptide compounds. As Barot et al state that the ester prodrug is the most common prodrug strategy, an artisan in this filed would attempt this modification with a reasonable expectation of success.
Finally, it would be obvious to optimize the length of the fatty alcohol used in the prodrug strategy, as Barot et al teaches that the lipophilicity of the drug can be optimized to maximize diffusion across the cornea while minimizing the amount that remains in the cornea. As this is a simple homologous series, an artisan in this field would attempt this optimization with a reasonable expectation of success.
Pang et al teach the SS-31 peptide for treatment of glaucoma. Barot et al render obvious making an ester prodrug, while Larsen et al render obvious attaching the ester at the C-terminus. Thus, the combination of references renders obvious claim 43.
Barot et al teaches that the length of the fatty alcohol must be optimized to allow diffusion through the cornea while not remaining in the cornea. Kabanov et al shows that longer lipid lengths may be necessary. This will mean a homologous series of fatty lipids, rendering obvious claims 48 and 75.
Larsen et al and Barot et al both discuss cleavage of the esters by carboxyesterases, rendering obvious claim 76.
Larsen et al discusses hydrolysis of the ester in PBS (a proxy for physiological conditions), rendering obvious claim 77.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 43, 48, and 75-78 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 32 and 40-42 of copending Application No. 18,566,629 in view of Pang et al (Med. Hypothesis Discov. Imnov. Ophthalmol. (2015) 4(3) p120-126) and Larsen et al (Eur. J. Pharmaceut. Sci. (2004) 22 p399-408).
Competing claim 32 specifies a formulation of a drug. Competing claim 40 specifies a prodrug formulation where the drug is linked via a cleavable bond to a Markush group of compounds, which include fatty alcohols. Competing claim 41 specifies a Markush group of bonds, including an ester bond. Competing claim 42 describes a Markush group of fatty alcohols, including stearoyl alcohol, applicant’s elected lipid.
The difference between the competing claims and the examined claims is that the competing claims do not describe the peptide sequence.
Pang et al teach that facet of glaucoma is optic nerve head cupping and visual field defects caused by apoptosis of retinal ganglion cells (RGC) (p120, 1st column, 1st paragraph), and that lowering the pressure, the standard therapy for the disorder, by itself, cannot prevent progressive loss of visual field (p120, 2nd column, 1st paragraph). At least part of this is due to mitochondrial dysfunction (p121, 1st column, 1st paragraph). A pharmacological agent that ameliorates oxidative stress and enhances RGCs mitochondrial function should be able to reduce the rate of visual field loss in glaucoma (p122, 1st column, 3d paragraph). SS-31 is suggested as an agent that will be successful in this role (p122, 2nd column, 1st paragraph). Note that this is the same sequence as applicant’s elected species, save for the C-terminal modification (compair fig 1, 122, 2nd column, bottom of page with applicant’s elected species). In a different optical disorder, the peptide was shown to protect RGCs (p123, 2nd column, 2nd paragraph). This reference discusses a drug for treating an ocular disorder.
Larsen et al discuss ester prodrugs to increase hydrophobicity of peptides for oil based depot formulations (abstract). While for a different purpose, this is the same principle as that described in Barot et al; esterification of a carboxylate with a fatty alcohol to increase lipophilicity, which can be cleaved off in vivo. The structure used a model peptide, Gly-Phe, with fatty alcohols of various lengths attached via an ester linkage to the C-terminus (fig 1, p401, 1st column, top of page). The rate of hydrolysis of the ester (not enzyme catalyzed) was inversely related to the length of the fatty alcohol (fig 4, p405, 1st column, bottom of page). While considerably enhanced, the same pattern was seen in human plasma (table 1, p406, 1st column, top of page), which is attributed to esterase cleavage (p406, 1st column, 2nd paragraph). This reference discusses ester prodrugs of peptides, using the C-terminal carboxylate as the binding site. This reference teaches attaching a fatty alcohol to a peptide via an ester linkage at the C-terminus.
Therefore, it would be obvious to use the drug of Pang et al for the drug of the competing claims, as a substitution of one known element for another yielding expected results. As the drug of the competing claims is generic, an artisan in this field would attempt this substitution with a reasonable expectation of success.
Furthermore, it would be obvious to attach the fatty alcohol to the C-terminus as an ester, as described by Larsen et al, as a substitution of one known element for another yielding expected results. As the competing claims describe a genus that includes this construct, an artisan in this filed would attempt this modification with a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FRED REYNOLDS whose telephone number is (571)270-7214. The examiner can normally be reached M-Th 9-3:30.
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/FRED H REYNOLDS/Primary Examiner, Art Unit 1658
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