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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on January 16, 2026 has been entered.
The Applicant's Amendment to the Claims filed on January 16, 2026 has been entered.
Claims 47-55 are new. Claims 1-26, 28, 33, 38-46 are cancelled.
Claims 27, 29-32, 34-37, and 47-55 are pending.
Claims 30-31, and 35-36 stand withdrawn to non-elected species.
New claims 47-49 are included in elected subject matter and examined.
New claims 50-55 are withdrawn to non-elected subject.
Claims 27, 29, 32, 34, 37, and 47-49 are under examination in this office action.
Response to Amendment
All rejections of presently cancelled claim 33 are rendered moot.
Please note that the Rule 132 Declaration of co-inventor Elia Duh mentioned in the “Remarks” filed on 01/16/2026 (page 8) has not been submitted as of 02/21/2026.
Priority
This US Application 17/194,177 filed on 03/05/2021 claims US priority benefit of US Provisional 62/985,811 filed on 03/05/2020.
Claim interpretation
GLP-1r agonists include the long-acting PEGylated exenatide (NLY01).
The term “treat” reads on management of a symptom with the intent to ameliorate or stabilize the symptom. (Instant specification, page 8, lines 21-24).
Claim Rejections - 35 USC § 112 - Scope of enablement
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.
Claims 27, 29, 32, 34, 37, and 47-49 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 the treating an animal model subject as shown in the Examples in the instant specification, does not reasonably provide enablement for treating glaucoma in a human patient where administering NLY01 provides remission of the glaucoma in the patient . 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 and 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 the method of treating an ocular disorder including glaucoma in a human patient.
The breadth of the claims: The base claim 27 is broad to treating any ocular disease or condition and all claims encompass the limitation of new claim 49 of treating a human patient for glaucoma where administering NLY01 provides remission of the glaucoma in the patient.
The state of the prior art and predictability in the art: The state of the prior art shows that pegylated exendin (EX-4) has been successful treating glaucoma in animal models and that NLY01 is closely related to exendin. However, the prior art but does not appear to disclose system administration of NLY01 resulting in treating a human patient for glaucoma where administering NLY01 provides remission of the glaucoma in the patient. See SIMÓ Canonge et al (US 2016/0000882 published 2016, now US Patent 9,707,273; of record).
The presence or absence of working examples and the amount of direction or guidance present: The guidance present in the specification is that of using NLY01 with animal mice models and primary cell cultures using microglia cells (See Examples 1-4). No non-rodent models were not shown. No results showing remission of glaucoma were shown
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. However, in view of the unpredictable nature of treating glaucoma in a human patient by systemic administration of NLY01, resulting in remission of the glaucoma, it is considered that the experimentation of to practice this invention as claimed would be undue.
The quantity of experimentation needed: The quantity of experimentation needed is undue because while in view of the instant specification and prior art it is a reasonable expectation for treating a glaucoma by systemic administration of NLY01 in a human patient, it is unknown whether remission of such glaucoma may be achieved in the patient.
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 determine whether glaucoma may be treated in a human patient resulting in remission of the glaucoma.
Claim Rejections - 35 USC § 103
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.
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.
Claims 27, 29, 32, 34, and 37 and new claims 47-48 are rejected under 35 U.S.C. 103 as being unpatentable over SIMÓ Canonge et al (US 2016/0000882 published 2016, now US Patent 9,707,273; of record), in view of Goncalves et al. (“Protective Effect of a GLP-1 Analog on Ischemia- Reperfusion Induced Blood-Retinal Barrier Breakdown and Inflammation”, IVOS, 2016, pp. 2584-2592; of record) in view of Park et al. (“Emerging PEGylated non-biologic drugs”, Expert Opinion on Emerging Drugs, 2019, 107-119; of record), Yun et al (“Block of Al astrocyte conversion by microglia is neuroprotective in models of Parkinson’s disease”, Nature Medicine, 2018, 931-938; of record) and Zeng et al. (“The role of microglia in the progression of glaucomatous neurodegeneration — a review”, Int J Ophthalmol, 2018, pp. 143-149; of record).
Regarding claims 27, 29, and new claim 47, Simo Canonge disclose topically administering in the eye a therapeutically effective amount of a peptide which is able reach the retina for the purpose of treating or preventing a retinal neurodegenerative disease in the eye of a subject in need thereof. See claims 1-19 and paras. [0022, 0023, 0028, 0055, 0068, 0069, 0074, 0099]. The peptide has a sequence length from 13 to 50 amino acids, the N-terminal region of the peptide has the sequence of SEQ ID NO: 1. See claims 1-19 and para. [0074]. Simó Canonge et al. teach all the peptides with a length of 13 to 50 amino acids and comprising at the N-terminal region the amino acid sequence consisting of SEQ ID NO: 1 are agonists of the GLP-1Rc. See para. [0074]. Simó Canonge et al. teach the peptide is SEQ ID NO: 2 (liraglutide), SEQ ID NO: 4 (exenatide) and SEQ ID NO: 8 (lixisentide). See reference claims 8, 18, 19; paras. [0064, 0074, 0073]; SEQ ID NOS: 2, 4 and 8. Simó Canonge et al. teach the retinal neurodegenerative disease is diabetic retinopathy, age-related macular degeneration, retinitis pigmentosa and glaucoma (elected species). See reference claims 3 and 16; para. [0055]. Therefore, the disclosures Simo Canonge et al meet the limitations of treating glaucoma (elected species) comprising administering to a subject a therapeutically effective amount of a glucagon-like peptide 1 receptor agonist, thereby treating glaucoma.
Regarding new claim 48, Simó Canonge et al. teach the administration and treating is to a human subject (see ref claims 20-21).
Regarding claim 37, Simó Canonge et al. teach the administration of liraglutide was in an amount significant enough to reduce (block) activation of microglia in the retina. (See paras. [0031, 0079, 0098, 0104-0106, 0111, 0112]; Fig. 3, Table 1.). Also, especially regarding claim 37, Goncalves et al teach exendin-4 acts to suppress microglia activation in models of retinal inflammation reducing subsequent vascular permeability. See page 2585, left col.-1" paragraph. However, Goncalves et al do not teach NLYO1 blocks activation of microglia in the eye.
Simó Canonge et al. teach the peptide is ref SEQ ID NO: 2 (liraglutide), 4 (exenatide) or 8 (lixisentide). ). (See reference claims 8, 18, 19; paras. [0064, 0074, 0073]; ref SEQ ID NOS: 2, 4 and 8).
However, Simo Canonge do not disclose NLY01 or systemic application.
Especially regarding claims 32, 34, and 47, Goncalves et al teach subcutaneously (systemically) administering exendin-4 (GLP- Ir agonist) to rat subjects with retinal ischemia-reperfusion (IR) injury. See page 2585, “Retinal Ischemia-Reperfusion”, 2nd paragraph. Goncalves et al teach subcutaneously (systemically) administering exendin-4 (GLP- Ir agonist) to rat subjects with retinal ischemia-reperfusion (IR) injury. See page 2585, “Retinal Ischemia-Reperfusion”, 2nd paragraph. The administration of exendin-4 attenuates characteristics of retinal diseases (ocular disease/disorders) such as protecting against the increase vascular leakage triggered by IR and attenuating microglial cell. See Figures 1, 4 and 5; page 2586, right col, Results, Ex-4 Prevents the Increase in BRB Permeability Induced by IR Injury; page 2589, left col, 3rd paragraph. The amount of exendin-4 administered taught by Goncalves et al is construed as a therapeutically effective amount that resulted in treating the ocular disease/disorder in rats with IR injury are susceptible to acquiring an ocular disease/disorder. Goncalves et al teach identifying a subject suffering from an ocular disease. Goncalves et al teach subcutaneously (systemically) administering exendin-4 (GLP- Ir agonist) to rat subjects with retinal ischemia-reperfusion (IR) injury. See page 2585, “Retinal Ischemia-Reperfusion”, 2nd paragraph. The administration of exendin-4 attenuates characteristics of retinal diseases (ocular disease/disorders) such as protecting against the increase vascular leakage triggered by IR and attenuating microglial cell. See Figures 1, 4 and 5; page 2586, right col, Results, Ex-4 Prevents the Increase in BRB Permeability Induced by IR Injury; page 2589, left col, 3rd paragraph. The amount of exendin-4 administered taught by Goncalves et al is construed as a therapeutically effective amount that resulted in treating the ocular disease/disorder in rats with IR injury are susceptible to acquiring an ocular disease/disorder. Further, Goncalves et al teach inflammation with blood-retinal barrier (BRB) barrier is a common feature of several retinal diseases. (See Abstract.) Goncalves et al teach ocular diseases, like retinal vascular occlusion, acute glaucoma, diabetic retinopathy, and retinopathy of prematurity, have been associated with retinal ischemia-reperfusion (IR) injury. See page 2584, left col, 1st paragraph. Goncalves et al teach exendin-4, a GLP-1 receptor agonist, has been shown to have neuroprotective effects in retinas. See page 2584, right col, continuing paragraph. Goncalves et al further teach data suggest exendin-4 acts to suppress microglia activation in models of retinal inflammation that results in reduced vascular permeability. See page 2585, left col, 1st paragraph. Goncalves et al teach evidence of retinal neurodegeneration, inflammation, including microglial activation, and BRB loss associated with tight junction alterations all may be observed after IR injury. See page 2589, left col, 3rd paragraph.
However, while Goncalves et al teach systemically administering the GLP-Ir agonist which is exendin-4, they differ from the present claims because they do not teach the GLP-Ir agonist NLYO1.
Park et al teach NLYO1 is an analog of exendin-4 with an exceptional half-life when compared to exendin-4. See Park et al., page 113, right col.-continuing paragraph and Yun et al., page 931, left col.-1“ paragraph.
Yun et al. teach NLYO1I retains comparable biological activity to exendin-4. See page 931, left col.-1“ paragraph. Yun et al teach the mechanism of action of NLYO1 is through microglia by preventing activation of microglia, which is consistent with reports that show exendin-4 prevents activation of microglia both in vitro and in vivo following a variety of injury paradigms. Further, Yun et al. cites the reference of Goncalves et al. See reference 27. See the abstract; page 937, left col.-1st paragraph. Further, Zeng et al. teach glaucoma is a retinal disease characterized by neuroinflammation. See the abstract, para titled: Microglia and Neuroinflammation in Glaucoma. Zeng et al. teach microglia become reactive and redistribute to the retina, optic nerve and optic track, contributing to the disease onset or progression of glaucoma. See pages 143-144, bridging paragraph. Zeng et al teach microglia activation in the eye plays a role in the pathogenesis of glaucoma. See the abstract; page 144, Microglia and Neuroinflammation in Glaucoma. Zeng et al. suggest targeting microglial cells in treating glaucoma. See page 146, Conclusion.
At the time of the effective filing date of the claimed invention, it would have been obvious to administer NLY01 to a subject identified as suffering from glaucoma because microglia activation plays an important role in the neuroinflammatory response of glaucoma. The artisan of ordinary skill in the art would have been motivated to administer NLYO1, an analog of exendin-4, because NLYO1 prevents microglia activation and has improved pharmacokinetic properties over exendin-4.
Regarding claims 32, 34, and new claim 47, Yun et al teach both exendin-4 and NLYO1 can be administered subcutaneously (systemically). See e.g., page 939, right col.-§Pharmacokinetic profile NLYO1 in cynomolgus monkeys and mice.
It would have been obvious at the time of the effective filing date of the claimed invention to administered NLYO1 subcutaneously (systemically) with a reasonable expectation of success because it has been demonstrated that it can be administered subcutaneously.
The artisan of ordinary skill would have been motivated to choose this mode of administration because NLYO1 has the same mechanism of action as exendin-4, the parent compound of NLYO1, but with better pharmacokinetically when administered subcutaneously (systemically).
Therefore, it is considered that one of ordinary skill in the art having the cited references would have had a reasonable expectation of success to combine the elements of the cited references to arrive at the presently claimed invention. Thus the claims as a whole would have been obvious to one of ordinary skill in the art.
Response to Arguments
The Applicants arguments filed on 01/16/2026 have been fully considered as they may relate to this new grounds of rejection but are unpersuasive. Applicant argues:
To address at least this deficiency of Gonçalves et al., the Office cites Park et al., to assert that NLY01 is an analog of exendin-4. See, Park et al., page 113, right col.-continuing paragraph.
In contrast to the Office's assertions, Park et al., do not teach that large molecular weight molecules can cross the blood-brain barrier and result in the treatment of ocular diseases. The Office cites Yun et al., in an attempt to cure at least these deficiencies.
However, this argument is unpersuasive because contrary to the argument, the examiner has not stated in the rejection that Park et al teach that large molecular weight molecules can cross the blood-brain barrier and result in the treatment of ocular diseases.
Further, the applicants argue:
However, Yun et al., is directed to treatment of neurologic disorders such as Alzheimer's disease and Parkinson's disease. See, Abstract.
The Office alleges that one of skill in the art would turn to Yun et al, to administer NLY01. However, neither reference teaches or discloses that NLY01 is effective in the treatment of ocular diseases or disorders. Accordingly, the combination of references fails to teach disclose or otherwise suggest the use of NLY01 in the treatment of ocular disorders.
However, this argument is unpersuasive because In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Yun et al teach the mechanism of action of NLYO1 is through microglia by preventing activation of microglia, which is consistent with reports that show exendin-4 prevents activation of microglia both in vitro and in vivo following a variety of injury paradigms. Park et al teach NLYO1 is an analog of exendin-4 with an exceptional half-life when compared to exendin-4. Goncalves et al further teach data suggest exendin-4 acts to suppress microglia activation in models of retinal inflammation that results in reduced vascular permeability. See page 2585, left col, 1st paragraph. Goncalves et al. teach evidence of retinal neurodegeneration, inflammation, including microglial activation, and BRB loss associated with tight junction alterations all may be observed after IR injury. See page 2589, left col, 3rd paragraph. In this case, the motivation to substitute NLYO1 taught by Yun et al. and Park et al. for exendin-4 in the method taught by Goncalves et al. is because NLYO1 has an exceptional half-life when compared to exendin-4 while retaining comparable biological activity to exendin-4 such as preventing activation of microglia. Thus, NLYO1 is well-suited for the treatment of retinal inflammation because it inhibits microglia activation that leads to decreased inflammation.
Lastly, the applicants address the newly added claims, stating:
Additionally, Applicant's claim 47 recites "administering the NLY01 provides remission of the glaucoma in the subject". Applicant's claim 52 recites "administering the NLY01 provides remission of the retinal neovascularization in the subject". Applicant's claim 55 recites "administering the NLY01 provides remission of the age-related macular degeneration in the subject". None of the cited documents suggest such remission of glaucoma, retinal neovascularization or age-related macular degeneration.
Further, the applicants argue the combination of Goncalves et al., Park et al. and Yun et al. and Zeng et al fails to teach or suggest the use of NLYO1 as a therapeutic in the treatment of ocular disorders and Zeng et al do not cure the deficiencies.
However, this argument is unpersuasive because Zeng et al suggest targeting microglial cells in treating glaucoma and Yun et al teach the mechanism of action of NLYO1 is through microglia by preventing activation of microglia, which is consistent with reports that show exendin-4 prevents activation of microglia both in vitro and in vivo following a variety of injury paradigms. Yun et al teach NLYO1I retains comparable biological activity to exendin-4. See page 931, left col.-1st paragraph. Further, the Yun et al cites the Goncalves et al reference. See reference 27. See the abstract; page 937, left col.-1st paragraph.
Applicant argues the combination of references fails to teach or suggest the use of NLYO1 as a therapeutic in the treatment of ocular disorders. In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, the motivation to substitute NLYO1 taught by Yun et al. and Park et al. for exendin-4 in the method taught by Goncalves et al is because NLYO1 has an exceptional half-life when compared to exendin-4 while retaining comparable biological activity to exendin-4 such as preventing activation of microglia. Thus, NLYO1 is well-suited for the treatment of retinal inflammation because it inhibits microglia activation that leads to decreased inflammation. Further, Zeng et al. teach glaucoma is a retinal disease characterized by neuroinflammation. See the abstract, para titled: Microglia and Neuroinflammation in Glaucoma. Zeng et al. teach microglia become reactive and redistribute to the retina, optic nerve and optic track, contributing to the disease onset or progression of glaucoma. See pages 143-144, bridging paragraph. Zeng et al teach microglia activation in the eye plays a role in the pathogenesis of glaucoma. See the abstract; page 144, Microglia and Neuroinflammation in Glaucoma. Zeng et al. suggest targeting microglial cells in treating glaucoma. See page 146, Conclusion.
In addition, the applicants’ argument that one of ordinary skill in the art would be dissuaded to administer a high molecular weight protein or peptide in light of Goncalves et al is unpersuasive because generally arguments of counsel cannot take the place of evidence on the record. Nothing in Goncalves et al teaches away from using NLYO1 which is evidenced by both Yun et al and Park et al to have an exceptional half-life when compared to exendin-4 while retaining comparable biological activity to exendin-4 such as preventing activation of microglia.
In addition, the applicants argue that the instant application discloses extensive in vivo data that demonstrates NLY01 is effective for treating ocular diseases and disorders, including glaucoma. (See Remarks page 9). However, this argument is unpersuasive regarding the rejection for obviousness over the combination of cited references because it does not address the differences over the cited prior art.
Conclusion
No claim is allowed.
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CATHERINE S. HIBBERT
Primary Examiner
Art Unit 1658
/CATHERINE S HIBBERT/Primary Examiner, Art Unit 1658