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 .
Status of the Claims
Claims 25-36, directed toward methods of treating diabetic retinopathy, are pending, presented for examination, and rejected as set forth in greater detail below.
Claim Interpretation
Applicants Claim 25 is directed to methods of treating diabetic retinopathy by intravitreally injecting an implant containing a defined quantity of edonentan every 3-6 months to a subject in need of treatment. Claim 26 specifies that the edonentan is crystalline, with Claim 27 indicating the treatment is to be provided during the non-proliferative stage of the disease. Claim 28 expands the breadth of Claim 25, indicating that the method simply delivers a therapeutically effective amount of an ophthalmic preparation of edonentan to the back of the eye every 3-6 months. Claim 29 requires crystalline edonentan, and Claim 30 that the edonentan of Claim 28 be delivered in a defined amount. Claims 31-35 specify that the patient experiences any of a number of post-administration responses to the delivery of the edonentan composition of Claim 28. Claim 36 is directed to a method of treating diabetic retinopathy by injecting a composition containing a therapeutically effective amount of edonentan into an optical tissue of a subject having DR.
Response to Amendment
The Declaration of inventor Gurkan under 37 CFR 1.132 filed 27 May 2026 is insufficient to overcome the rejection of claims 25-36 based upon the teachings of Mashima, Gulati, and Ahlheim, either alone or in further combination with the teachings of Boscia as set forth in the last Office action because the Gurkan declaration again fails to provide sufficient evidence to either contradict the Examiner’s conclusions concerning the obviousness of the method of treating diabetic retinopathy with an injectable edonentan implant, or to establish any unexpected results are obtained by the practice of the method claimed.
Dr. Gurkan again sets forth arguments predicated on references available to the skilled artisan only after the effective filing date of the present application. Applicants are again reminded that the question of the obviousness of an invention is addressed by reliance only on knowledge available to the skilled artisan at the time the application in question was filed. See MPEP 2141.01(III). As such, arguments predicated on the teachings of any and all of the Sun, Maturi, and Maguire references are moot owing to the fact that each of these publications post-date the effective filing date of the present application.
Dr. Gurkan’s assertion that the observed improvement in visual acuity is somehow unexpected is contradicted by the knowledge available to the skilled artisan at the time the instant application was filed. As was set forth in the office action mailed 2 May 2023 in the parent 17/733,210 application, at the time the instant application was filed, endothelin-A selective antagonists such as edonentan were known to effect anti-ischemic effects. See Martin Hulpke-Wette & Reiner Buchorn, BMS-0190884 and BMS-207840 Bristol-Myers Squibb, 3 Curr. Opin. Invest Drugs (2002) (demonstrating that BMS-207940, the proprietary name for edonentan, demonstrates a profound selectivity for the endothelin-a receptor), Anna-Leena Siren, et al, Endothelin B Receptor Deficiency Augments Neuronal Damage Upon Exposure to Hypoxia-Ischemia in Vivo, 945 Brain Res. 144 (2002) (establishing that endothelin-A receptor antagonists improved hypoperfusion and neuronal survival in rodent models of ischemia)(each of record in parent application). When combined with additional knowledge available at the time, such as that provided by Sim (Dawn A. Sim, et al, The Effects of Macular Ischemia on Visual Acuity in Diabetic Retinopathy, 54 IOVS 2353 (2013)), macular ischemia was known to be an important factor in the impairment of visual acuity in people suffering diabetic retinopathy. The art then establishes not only that endothelin antagonists including the endothelin-A selective antagonist edonentan were taught to be useful in the treatment of complications of diabetes, and more specifically diabetic retinopathy, but that the anti-ischemic attributes of endothelin-A antagonists were also well-known, as was the connection between macular ischemia and loss of visual acuity in diabetic retinopathy. It must be remembered that if an applicant merely submits evidence to establish the obtention of a result which would have been expected based upon the knowledge of the worker in the art, the evidence merely buttresses the Examiner’s case for obviousness. In re Skoll, 523 F.2d 1392, 187 USPQ 481, 484 (CCPA 1975). Because neuropreservation in a model of ischemia-hypoxia would have been what a skilled artisan would have expected to see from the administration of a known endothelin-a antagonist such as edonentan, the data presented by the Gurkan declaration cannot serve to establish the non-obviousness of such a method.
Inventor/declarant Gurkan is reminded that the reason or motivation to modify a prior art reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006) (motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention). As such, the discussion put forth concerning the alleged “paradox” of endothelin receptor antagonists relative to vasoconstriction or vasodilation is irrelevant to the question of the obviousness of the method claimed, which applicants are reminded is the treatment of diabetic retinopathy. Applicants assertion that the art of record fails to identify which endothelin receptor should be targeted in the treatment of diabetic retinopathy. This is inaccurate, as Gulati establishes a preference for endothelin-A receptor antagonists in the treatment of complications of diabetes. Col.5, L.46-49. That an embodiment of an endothelin receptor antagonists described by Gulati decreased perfusion in brain tissue is irrelevant to the case of treatment of diabetic complications such as retinopathy, owing to the fact that endothelin receptor antagonists are known to exert different activities on different tissues. See Gulati Col.2, L.19 – Col.3, L.27. The art of record amply supports the examiner’s conclusion concerning the obviousness of using endothelin receptor A antagonists such as the presently claimed edonentan in the treatment of diabetic retinopathy; nothing more is required to shift to the applicants the burden of demonstrating secondary indicia of nonobviousness.
For at least these reasons, the latest Gurkan declaration is unpersuasive.
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 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.
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.
Claims 25, 26, 28-30, and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Mashima (U.S. PGPub 2011/0275715), in view of Gulati (U.S. 8,980,874), and Ahlheim (U.S. PGPub. 2004/0234611).
Mashima describes methods for treating retinal diseases in a patient in need thereof. (Abs.). Delivery of the therapeutic agent to the vitreous is specifically described. [0014]. More specifically, delivery of the therapeutic agent such as an endothelin antagonist via injection to the back of the eye for the treatment of neuro-degenerative ophthalmic diseases is described. [0018] (Pg. 4-5, paragraphs (73; 75; 92; and 102), see also [0066]. Delivery to the vitreous body is described, [0014; 0066], as is subretinal delivery. [0173]. Diabetic retinopathy is a specifically enumerated disease to be treated. [0006; 0018; 0143] (Claim 27). Endothelin antagonists are specifically recited as useful active agents to incorporate into such treatment methods. [0064].
Despite this breadth of teaching, Mashima does not enumerate the instantly claimed edonentan as a particular Endothelin antagonist for use in the methods of treating diabetic retinopathy suggested.
This is cured by the teachings of Gulati, which establishes that the instantly claimed edonentan was at the time known to be an endothelin antagonist useful in the treatment of diabetic complications. (Col.5, L.58-60). Gulati describes therapeutically effective amounts of endothelin antagonists as determinable by a physician; while this does not specify the dosages particularly recited by Claims 25 or 30, this establishes that the dosage is a result-effective variable optimizable by a skilled physician. (Col.7, L.8-51). As a result, the dosages of Claims 25 and 30 must be considered obvious as little more than routine optimization by a skilled artisan. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (indicating that where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.).
It would have been prima facie obvious for one having ordinary skill in the art at the time of the instant application to have intravitreally injected edonentan as an endothelin antagonist in the treatment of diabetic retinopathy. One having ordinary skill in the art would have been motivated to do so because Mashima suggests that the intravitreal injection of endothelin antagonists serves to treat diabetic retinopathy, and Gulati establishes that edonentan is known to be an endothelin antagonist useful in the treatment of diabetes-related complications. The selection of edonentan as the endothelin antagonist in the methods of treating diabetic retinopathy suggested by Mashima amounts to little more than the selection of a known material for use in a method based on its recognized suitability for its intended use. See Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).
Neither Mashima nor Gulati describe employing a crystalline version of the Endothelin antagonist, nor is a particular dose, targeting vehicle, or window within which a readministration of the endothelin antagonist may take place specified.
This is cured by the teachings of Ahlheim, which describes ophthalmic nanoparticle formulations of active agents embedded in lipid encapsulating agents. [0007]. Ahlheim recites crystalline forms of the active agent as includable in the dosage forms described. [0010]. Ahlheim indicates that these nanoparticles are designed to release the agents contained therein within periods of time of several weeks and up to six months when delivered to the retina or vitreous. [0012; 0066]. Applicants are reminded that simply repeating process steps is prima facie obvious in the absence of new and unexpected results. See In re Harza, 274 F.2d 669, 124 USPQ 378 (CCPA 1960). Because Ahlheim describes the ophthalmic compositions as capable of releasing agent for up to six months, it would have been prima facie obvious to repeat administration of such a formulation every six months, per the requirements of Claims 25 and 28. Ahlheim describes these compositions as being injectable, with endothelin antagonists specifically recited as active agents suitable for inclusion in such compositions. [0029; 0034]. Ahlheim enumerates diabetic retinopathy as among the diseases suitably treated by such compositions and methods. [0052].
It would have been prima facie obvious to have formulated the endothelin antagonist injections suggested by the teachings of Mashima and Gulati to contain crystalline edonentan in a nanoliposome formulated for injection every six months per the teachings of Ahlheim for the treatment of diabetic retinopathy. This is because, per the teachings of Mashima, Gulati, and Ahlheim, it must be remembered that “[w]hen a patent simply arranges old elements with each performing the same function it had been known to perform and yields no more than one would expect from such an arrangement, the combination is obvious.” KSR v. Teleflex, 127 S.Ct. 1727, 1740 (2007) (quoting Sakraida v. A.G. Pro, 425 U.S. 273, 282 (1976)). “[W]hen the question is whether a patent claiming the combination of elements of prior art is obvious,” the relevant question is “whether the improvement is more than the predictable use of prior art elements according to their established functions.” (Id.) Here, Ahlheim describes the compositions and methods as suitable for addressing the difficulty of ocular drug delivery and maintenance of therapeutically effective amounts of drug for the treatment of ocular diseases, which would serve to improve the treatment of diabetic retinopathy suggested by the teachings of Mashima and Gulati. [0002; 0005]; see also In re Sernaker, 702 F.2d 989, 994-95 (Fed. Cir. 1983) (“The strongest rationale for combining references is a recognition, expressly or impliedly in the prior art or drawn from a convincing line of reasoning based on established scientific principles or legal precedent, that some advantage or expected beneficial result would have been produced by their combination.”).
Claims 25-36 are rejected under 35 U.S.C. 103 as being unpatentable over Mashima, Gulati, and Ahlheim as applied to Claims 25, 26, 28-30, and 36 above, and further in view of Boscia (Francesco Boscia, Current Approaches to the Management of Diabetic Retinopathy and Diabetic Macular Oedema, 70 Drugs 2171 (2010))(of record in parent).
Mashima, Gulati, and Ahlheim, discussed in greater detail above, suggest the repeated subretinal injection of edonentan nanoliposomes for the treatment of diabetic retinopathy. However, none of Mashima, Gulati, and Ahlheim specify treatment during a non-proliferative phase of the disease, or the means of ascertaining the efficacy of the diabetic retinopathy treatment being provided.
This is cured by the teachings of Boscia, which establish that clinical findings of DR can range in severity according to the degree of vascular abnormality, with non-proliferative DR being the earlies stage of the disease, which if untreated can progress to severe proliferative DR, suggesting both the timing of treatment recited by Claim 27, as well as the severity assessment of Claim 31. (2173-74). Macular edema of Claim 35, representing intraretinal perfusion of Claim 34, (2173), retinal neurodegeneration of Claim 33 (2175), as well as the loss of visual acuity (2174), were known at the time of the instant application to skilled clinicians as means of determining the progression, or regression, of diabetic retinopathy severity. (Pg. 2173, 2175-76),
Because the art at the time of the instant application acknowledges each of the clinical findings recited by the instant Claims as manifestations of the clinical progress of diabetic retinopathy, it would have been prima facie obvious for a skilled artisan to assess changes in any or all of these signs, symptoms, or complications as evidence of the efficacy of methods of treating diabetic retinopathy such as those suggested by the combined teachings of Mashima, Gulati, and Ahlheim.
Response to Arguments
Applicant's arguments filed 27 May 2026 have been fully considered but they are not persuasive.
Applicants arguments reiterating the positions set forth in the Gurkan declaration are unpersuasive for the reasons set forth in greater detail above.
Applicants assertion that neither the Mashima nor Gulati references establish exactly which endothelin antagonists would be effective in the treatment of diabetic retinopathy is unpersuasive. As set forth previously and again above, the art of record establishes that endothelin antagonists may be used in the treatment of diabetes, complications of diabetes, and diabetic retinopathy, as well as the fact that edonentan is an endothelin-A antagonist known to be useful in the treatment of diabetes. Nothing more is required to establish a prima facie case of obviousness, as it has long been held that it is prima facie obvious to select a known material for use in a method based on its recognized suitability for its intended use. See Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945) (indicating that "Reading a list and selecting a known component to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle. It is not invention.”); see also Merck & Co., Inc. v. Biocraft Labs., Inc., 874 F.2d 804, 807 (Fed. Cir. 1989); In re Corkill, 771 F.2d 1496, 1500 (Fed. Cir. 1985) (holding that it is well settled that it is a matter of obviousness for one of ordinary skill in the art to select a particular component from among many disclosed by the prior art as long as it is taught that the selection will result in the disclosed effect, even when the possible selections number 1200 or in the thousands); In re Rinehart, 531 F.2d 1048, 189 USPQ 143 (CCPA 1976) (obviousness does not require absolute predictability).
Applicants reassertion of the argument set forth by declarant Gurkan concerning teaching away from using an endothelin antagonist in the treatment of diabetic retinopathy is no more persuasive upon its repetition. Applicants attention is directed to the Examiner’s discussion of this argument in the rebuttal of the Gurkan Declaration.
For at least these reasons, applicants arguments are unpersuasive.
Conclusion
No Claims are allowable.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SEAN M BASQUILL whose telephone number is (571)270-5862. The examiner can normally be reached Monday through Thursday, 5:30 AM to 4 PM.
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/SEAN M BASQUILL/Primary Examiner, Art Unit 1614
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