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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 10 April 2026 has been entered.
Status of the Claims
Claims 1-3, 5-7, and 11-32 are pending.
Claims 11-30 are withdrawn from consideration as directed to non-elected inventions.
Claims 1-3, 5-7, 31, and 32 are presented for examination and rejected as set forth below.
Claim Interpretation
Applicants claims are directed to compositions containing particles of a defined size, less than 1 micron, either or both of tacrolimus or what applicants refer to as the “tacrolimus 10-epimer,” combined with each of PEG40 stearate, hydroxypropyl-β-cyclodextrin, an emollient, and a buffer to provide a suspension having a defined contact angle, to provide a composition “employable as an eye drop. Applicants are reminded that language defining a manner in which a composition may be used does not limit the invention claimed. Boehringer Ingelheim Vetmedica, Inc. v. Schering-Plough Corp., 320 F.3d 1339, 1345 (Fed. Cir. 2003)(indicating that a recitation of an intended use will not limit the scope of the claim because it merely defines a context in which the invention may operate). Applicants claims require that the composition containing these elements lacks a preservative. What applicants refer to as the “10-epimer” is shown below.
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This appears to correspond to the compound referred to by skilled artisans as the “Tacrolimus 19-epimer,” CAS RN144490-63-1, shown below.
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Dependent claims narrow the amount of emollient present, define the pH of the composition, irradiates any or all of the components of the composition, narrow the amount of PEG, or viscosifier, or buffer.
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.
Claims 1-3, 5-7, 31, and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Popov (WO2013/166436), in view of Ni (CN 112770724, Bullock (WO2020/165839), and Liu (Hanyu Liu, et al, Wettability and Contact Angle Affect Precorneal Retention and Pharmacodynamic Behavior of Microspheres, 28 Drug Del. 2011 (2021).
Popov describes particulate compositions useful for the delivery of drugs to the eye, such as by an eye drop. (Abs.); [000284; 000344; 000354]. Indeed, Popov indicates that eye drop formulations capable of maintaining a high concentration of the agent for extended periods of time at the ocular surface are desirable, making the amount of agent included in such eye drop formulations a result-effective variable suitable for optimization through nothing more than the routine experimentation of a skilled artisan, rendering the amount of drug present in a single eye drop recited by the newly amended claims prima facie obvious. [000347-48]; 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.). Popov indicates these particles may be a solid pharmaceutical agent, and in some embodiments represents 100% of the core. [000104-05]. Popov indicates that these compositions possess a contact angle of between 60 and 80 degrees. [000111]. While this value is not measured in the manner set forth by the present claims, nor does it pertain to the composition as a whole, applicants are directed to the teachings of Liu, which establishes that contact angles of particulate ophthalmic suspensions positively correlate with increased retention time of the compositions applied to the ocular surface, also positively correlating to the efficacy of any agents so formulated for ocular delivery. (Pg. 2018). As such, the skilled artisan would recognize the contact angle recited or implied by Claims 1 and 32 as result-effective variables suitable for optimization employing little more than routine experimentation. See Aller, supra. The core particles are described by Popov as having diameters within a range of about 1-5 microns, a range overlapping and therefore rendering obvious the limitations of Claim 8. [000129], See Peterson, supra. Popov specifically indicates that the tacrolimus of the instant claims may serve as the active pharmaceutical agent. [000260; 000444; 000450]. Popov indicates that for topical application to the eye, the compositions containing the active agent particles may be formulated as eye drops containing any conventional additives, including but not being limited to buffering agents, tonicity adjusting agents, viscosity modifiers, or suspension stabilizers. [000284]. Preservative-free eye drops are specifically recited as an option for the topical ophthalmic eye drop formulations described. [000441]. Glycerin, and more specifically glycerin in concentrations of greater than 0.1% and less than about 10%, is recited as an exemplary tonicity agent, addressing the limitations of Claim 2. [000314-15; 000471]. Sterile products are capable of being provided by gamma irradiation, more particularly indicating that any of the individual components of a formulation may be sterilized by gamma irradiation, and more specifically stating that the particles of active agent themselves may be individually sterilized by irradiation. [000326-27; 000332]. For ocular administration, Popov indicates the compositions should have a pH not irritating to the eye, such as a mildly basic pH of about 8, addressing the limitations of Claim 3. [000382].
Popov therefore suggests formulating particles of tacrolimus having a diameter of about 1 micron in a preservative free eye drop formulation along with conventional ophthalmic additives such as 0.1-10% glycerin, buffers to bring the pH to about 8, as well as viscosity modifiers, or suspension stabilizers, to name a few. Popov does not, however, specify that the eye drop composition should include PEG 40 Stearate, HPMC, hydroxypropyl-β-cyclodextrin, or any of the specific buffers recited by Claim 7 as eye drop components.
This is cured by the teachings of Ni, which while describing them in the context of a sterile, preservative-free eye drop composition for the delivery of a multi-kinase inhibitor, establishes that at the time of the instant application these components were conventional eye drop ingredients. Specifically, the hydroxypropyl-β-cyclodextrin newly added to Claim 1 as well as the polyethylene glycol 40 stearate recited by Claim 5 are described as an ophthalmically suitable solubility enhancer and surfactant, respectively, where the surfactant is usefully included in the claimed concentration range of about 0.01-10%. (Pg.2). Thickeners such as the HPMC of Claim 6 are recited as usefully included in concentrations of the claimed range of about 0.01-10%. (Id.). The phosphates of Claim 7 are described as usefully providing a pH in the range of 4.0-8.0, (Id.), but more specifically to be included in concentrations of about 0.01-1%, a range overlapping and rendering obvious that of the instant claims. (Pg. 5). Glycerol in concentrations of about 0.1-10% is described as a suitable tonicity adjusting agent. (Pg.2). Ni again indicates these compositions may be preservative free. (Pg.3). Ni also indicates that squalene is a commonly employed lipophilic carrier to be used in topical ophthalmic emulsion , usually present in concentrations of between about 0.001-10% by weight. (Pg.10).
It would have been prima facie obvious to have combined hydroxypropyl-β-cyclodextrin as a solubility enhancer with the claimed quantities of polyethylene glycol 40 stearate, HPMC, phosphate buffers, and glycerol into a preservative free eyedrop containing tacrolimus particles sterilized via gamma irradiation of between 1-5 microns having a pH of about 8 to be used as a topical ophthalmic eye drop. This is because Popov suggests formulating particles of tacrolimus having a diameter of about 1-5 microns and sterilizing them via gamma-irradiation in preservative free eye drop formulation along with conventional ophthalmic additives, which Ni establishes the remainder of the elements set forth by the claimed compositions are nothing more than. 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.). Because the teachings of Popov and Ni establish the claimed combination of tacrolimus particles, viscosifiers, dispersants, emollients, hydroxypropyl-β-cyclodextrin, and buffers were known to be useful in providing sterilized preservative free eye drops, the compositions claimed are prima facie obvious over the art relied upon.
Popov and Ni, discussed in greater detail above, suggest topical preservative-free eye drops combining polyethylene glycol 40 stearate, hydroxypropyl-β-cyclodextrin, viscosity agents such as HPMC, phosphate buffers, and glycerol solutions containing sterilized tacrolimus particles of about 1 micron having a pH of about 8, but fail to describe a particular viscosity the eye drops are to possess.
This is cured by the teachings of Bullock, which in the context of alternative eye drop formulations (passim), indicates that maintaining appropriate suspension viscosity, such as between about 10-200 cP, a range overlapping and therefore rendering obvious that of Claim 9, beneficially maintains particulates in a suspended state in the formulation without settling. (Pg.25).
It would have been prima facie obvious to have formulated the eye drops suggested by the teachings of Popov and Ni to have a viscosity overlapping that of the instant claims. This is because Bullock indicates an advantage is to be gained by such viscosity of eye drop formulations. See 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.”).
Response to Arguments
Applicant's arguments filed 10 April 2026 have been fully considered but they are not persuasive.
Applicants argue that the compositions of the instant claims are not directed to a formulation that comprises a core-coated particle and are therefore distinct from the compositions of Popov. This is unpersuasive because even if applicants assessment of the totality of the Popov disclosure is accurate, a position the Examiner does not concede, such an argument would be irrelevant, as nothing of the compositions claimed, which “comprise” the recited elements, would exclude a coated particle. Genentech, Inc. v. Chiron Corp., 112 F.3d 495, 501, 42 USPQ2d 1608, 1613 (Fed. Cir. 1997) ("Comprising" is a term of art used in claim language which means that the named elements are essential, but other elements may be added and still form a construct within the scope of the claim.).
Applicants argument that somehow the absence of the term “solid” from the Ni disclosure precludes the Examiner from relying on any of its teachings, despite the established analogy of their teachings, finds basis in neither law nor evidence and on this basis unpersuasive. The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 1470, 43 USPQ2d 1362 (Fed. Cir. 1997).
Moreover, applicants arguments concerning the incompatibility of emulsions and coated nanoparticles, again devoid of supporting evidence and unpersuasive per se as a result, further evinces unawareness of Pickering emulsions, emulsions stabilized by the inclusion of nanoparticulates. Yves Chevalier & Marie-Alexandrine Bolzinger, Emulsions Stabilized with Solid Nanoparticles: Pickering Emulsions, 439 Coll. Surf. A: Physiochem;. Eng. Aspects 23 (2013). As such, applicants assertion that the particles of Popov would somehow be incompatible with Ni is incompatible with the knowledge available to the skilled artisan, even before understanding that this argument misapprehends the rationale for the Examiner’s reliance on their teachings. Again, that is to establish that the elements missing from the teachings of Popov are, nevertheless, ingredients commonly employed in eye drop compositions to provide to those compositions various properties desirable in eye drops. Applicants again commit the error of presuming that the entirety of a prior art reference be incorporated into the other references relied on, rather than focusing on what the art, considered as a whole, conveys. The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981), In re Kotzab, 217 F.3d 1365, 1370 (Fed. Cir. 2000). Moreover, the inventor declarant is reminded that the scope of analogous art is to be considered broadly. Wyers v. Master Lock Co., No. 2009-1412, 2010 WL 2901839 (Fed. Cir. July 22, 2010). Analogous art is not limited to references in the field of endeavor of the invention, but also includes references that would have been recognized by those of ordinary skill in the art as useful for the desired purpose. Agrizap, Inc. v. Woodstream Corp., 520 F.3d 1337 (Fed. Cir. 2008). As each of the relied upon references concern compositions for ocular delivery of active agents, the analogy of the art, and the basis for reliance thereupon, is evident. As such, the compounds and compositions taught by the art, whether it be Ni or Popov, describing various beneficial properties contributed to topical eye drop formulations by the inclusion of those components, remains a valid rationale for their combination and inclusion.
Applicants arguments concerning the teachings of Bullock and Liu continue the pattern of ignoring the rationale provided on record for the reliance on the knowledge conveyed thereby. Neither Bullock nor Liu are relied on to teach the compatibility of particles of active agent with additional ophthalmic composition excipients.
For at least these reasons, applicants arguments are unpersuasive.
Conclusion
No Claims are allowable.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ali Soroush can be reached at (571) 272-9925. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SEAN M BASQUILL/Primary Examiner, Art Unit 1614
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