DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after 16 March 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Replacement Drawings sheets, Amendments to the Claims and Arguments/Remarks filed 06 April 2026, in response to the Office Correspondence dated 07 January 2026, are acknowledged.
The listing of Claims filed 06 April 2026, have been examined. Claims 1-10, and 12-20 are pending. Claims 1, 5-10, and 12-20 are amended and are supported by the originally-filed disclosure. Claim 11 is canceled and no new claims have been added.
Information Disclosure Statement
The Information Disclosure Statement, filed 06 April 2026, is acknowledged and has been considered.
Response to Amendment
The applicant’s submission of replacement drawing sheets is acknowledged. The objection to drawing quality is hereby withdrawn. The objection to claims 5 and 11 as redundant is moot in view of the cancellation of claim 11 and is hereby withdrawn. The rejection of claims 1-20 under 35 U.S.C. § 112(a) based on the term “stable” is hereby withdrawn in view of the applicant’s amendment to the claims to remove the term “stable” from the claims.
The rejection of claims 7, 9, 10, and 13-20 under 35 U.S.C. § 112(a) for lack of written description is maintained. The applicant’s traverse is noted but is respectfully understood but the rejection is maintained because of the lack of XRD experimental conditions in the specification. The applicant’s reliance on general principles of X-ray diffraction is insufficient to cure the written description deficiency. While the applicant correctly notes that characteristic XRD peaks correspond to crystal lattice spacing, the specification fails to disclose the operational parameters under which the claimed peak positions were measured.
As a matter of written description, one of ordinary skill in the art is not informed whether the recited 2-theta values were obtained using Cu Kα radiation (the most common source, but not the only source), a specific wavelength, a particular scan rate, or under controlled humidity conditions. These parameters materially affect peak positions and can cause 2-theta values to vary depending on instrumentation and methodology. The specification does not incorporate by reference any standard XRD protocol, nor does it provide the raw data or instrument settings used to generate the patterns in Figure 2. The LibreTexts and Technology Networks citations provided by applicant are extrinsic to the specification as filed and cannot cure a written description deficiency unless they are incorporated into the specification by amendment.
The applicant’s argument with respect to reciting formulations that are “substantially free of” certain other cyclosporine forms is persuasive. The applicant correctly notes that “substantially free” is explicitly defined in the specification at ¶[0210]. Therefore, the rejection has been withdrawn.
The rejection of claims 1-20 under 35 U.S.C. § 112(b) based on “sodium hydroxide/hydrochloric acid” and “stable” is hereby withdrawn in view of the applicant’s amendment to “sodium hydroxide and/or hydrochloric acid” and the removal of “stable” from the claims.
The rejection of claims 7, 9, 10, and 13-20 under 35 U.S.C. § 112(b) indefiniteness is maintained. While the applicant correctly notes that XRD patterns serve as “fingerprints” for crystalline phases, the failure to specify relative intensities for the claimed peaks renders the claims indefinite. A person of ordinary skill in the art cannot determine which peaks among the XRD pattern are “characteristic” without guidance on minimum relative intensity. For example, a peak at 2-theta 6.9° may be the most intense peak (100% relative intensity) in one polymorph but a minor peak (5% relative intensity) in another. The claim provides no objective boundary. The applicant’s citation to “X-Ray Diffraction (XRD) – XRD Principle” is extrinsic evidence and does not cure the intrinsic deficiency. The claim must be definite on its face, not by reference to external tutorials that were not incorporated into the specification. Accordingly, the rejection under 35 U.S.C. § 112(b) is maintained.
Regarding the rejection of claims 1, 5, and 8 under 35 U.S.C. § 103 as being unpatentable over Weiss, claims 1 and 2 under 35 U.S.C. § 103 as being unpatentable over Weiss in view of Takruri, claims 1, 3 and 4 under 35 U.S.C. § 103 as being unpatentable over Weiss in view of Weiss2, claims 1, 5, 6, 11 and 12 under 35 U.S.C. § 103 as being unpatentable over Weiss in view of CEQUA cyclosporine ophthalmic solution FDA labeling information, claims 1, 5, 7, 9, 10 13, 14, 17 and 18 under 35 U.S.C. § 103 as being unpatentable over Weiss in view of Gore, and claims 13, 15, 17, 19 and 20 under 35 U.S.C. § 103 as being unpatentable over Weiss in view of Gore in further view of CEQUA cyclosporine ophthalmic solution FDA labeling information are maintained. The applicant arguments are not persuasive as detailed further below in the Response to Arguments.
Regarding the provisional statutory and nonstatutory double patenting rejections of claims 1-11 under 35 U.S.C. § 101 over claims 25-34 of co-pending US Application No. 18/683,932 and claims 12-20 over claim 25-34 of co-pending US Application No. 18/683,932, respectively, the applicant states that claims 25-34 of co-pending US Application No. 18/683,932 have been cancelled. The applicant is advised to provide official confirmation of cancellation (e.g., a copy of the Notice of Allowance or an updated file history) to demonstrate that the reference application no longer presents a double patenting issue.
The provisional § 101 rejection is therefore moot, however the nonstatutory double patenting rejection of claims 12-20 over claims 25-34 of the co-pending US Application No. 18/683,932 is maintained. The applicant’s requested deferral of addressing the nonstatutory double patenting rejection until all other rejections have been overcome is denied. The applicant is reminded that this rejection may be overcome by filing a terminal disclaimer in compliance with 37 CFR 1.321, or by demonstrating that the claims are patentably distinct from the claims of the reference application.
Maintained Rejections
The following rejections are maintained from the previous Office Correspondence dated 07 January 2026, since the art which was previously cited continues to read on the amended/newly cited limitations.
Claim Rejections - 35 USC § 112(a)
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 7, 9, 10 and 13-20 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.
Claims 7, 9, 10, 13, and 17 recite cyclosporine forms defined by specific X-ray diffraction (XRD) peak positions and further recite formulations that are “substantially free of” certain other cyclosporine forms. However, the specification does not adequately describe the experimental conditions under which the XRD data were generated (e.g., radiation source, wavelength, scan rate, sample preparation, humidity control, or baseline correction), the acceptable variability or tolerance for the claimed peak positions. Absent such disclosure, the specification fails to comply with the written description requirement for the claimed solid-state forms across the full scope of the claims, particularly given the known polymorphic and amorphous variability of cyclosporine.
One of ordinary skill in the art is not informed whether the recited 2-theta values were obtained using Cu Kα radiation (the most common source, but not the only source), a specific wavelength, a particular scan rate, or under controlled humidity conditions. These parameters materially affect peak positions and can cause 2-theta values to vary depending on instrumentation and methodology. Claims directed to polymorphic forms defined solely by XRD peak positions require sufficient disclosure of measurement conditions to enable a skilled artisan to identify the claimed form with reasonable certainty (see Ex parte Kamen, 2013 WL 5945737 (PTAB 2013)). The specification does not incorporate by reference any standard XRD protocol, nor does it provide the raw data or instrument settings used to generate the patterns in Figure 2.
Dependent claims 14-16 and 18-20 are included in this rejection because they do not cure the defect noted above. To overcome this rejection, the applicant may consider amending the specification to include the XRD measurement conditions (e.g., radiation source, wavelength, scan rate, sample preparation) or amending the specification to incorporate these parameters by reference to a standard protocol.
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 Applicant regards as his invention.
Claims 7, 9, 10 and 13-20 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, regards as the invention.
Claims 7, 9, 10, and 13-20 are rejected under 35 U.S.C. § 112(b) as being indefinite. Claims 7, 9, 10, 13 and 17 recite XRD peak positions using the term "characteristic XRD peaks." This language is indefinite. The claims identify specific 2-theta values but do not specify relative intensity, which is a critical parameter for identifying a crystalline form by X-ray diffraction. A peak at a given 2-theta position may be minor or major; the claim does not specify what constitutes a "characteristic" peak (e.g., a peak with intensity greater than 5% of the most intense peak). Furthermore, the claim does not specify the measurement conditions (e.g., radiation source, sample preparation).
The Federal Circuit has held that claims reciting XRD peaks without relative intensities are indefinite where the specification does not provide the complete diffraction pattern or otherwise define “characteristic” (see Ex parte Kamen, 2013 WL 5945737 (PTAB 2013)). Figure 2 provides representative patterns but does not label which peaks correspond to which claimed 2-theta values, nor does it indicate the relative intensities of the identified peaks. A claim that requires infringers to guess which peaks the patentee considers “characteristic” does not satisfy the definiteness requirement of Nautilus, Inc. v. Biosig Instruments, Inc., 572 U.S. 898, 910 (2014), requiring claims to inform the public of the invention’s boundaries with reasonable certainty.
Dependent claims 14-16 and 18-20 are included in this rejection because they do not cure the defect noted above. To overcome this rejection, the applicant may amend the claims to specify relative intensities of the recited peaks or another specified threshold relative to the most intense peak in the pattern, or incorporate by reference a standard measurement protocol with intensity criteria in the specification.
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-AlA 35 U.S.C. § 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AlA) 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 1, 5, and 8 are rejected under 35 U.S.C. § 103 as being unpatentable over Weiss et al. (US10918694B2; published 16 February 2021, hereinafter referred to as “Weiss”).
Weiss teaches compositions, methods of making and using ophthalmic formulations comprising 0.087-0.093 wt % of cyclosporine, wherein in some aspects and embodiments the formulations may include nanomicelles, a polyoxyl lipid or fatty acid (e.g., hydrogenated 40 polyoxyl castor oil), and/or a polyalkoxylated alcohol (e.g., octoxynol-40) (Abstract) that, “…can be unexpectedly stable, for example, in large scale manufacturing… The formulations of the present disclosure in certain embodiments are surprisingly stable at high temperatures, for example, temperatures above about 40 degrees C.” (page 1, column 1, lines 59-60 to column 2, lines 1-3). Weiss further teaches in some aspects, formulations comprise 0.089-0.093 wt % cyclosporine, about 1.0 wt % hydrogenated 40 polyoxyl castor oil, about 0.05 wt % octoxynol-40 (Igepal), about 0.20-0.405 wt % sodium phosphate monobasic, about 0.23-0.465 wt % sodium phosphate dibasic, about 0.05 wt % sodium chloride, about 0.3 wt % povidone K90, sodium hydroxide/hydrochloric acid to adjust the pH to about 5-8, and water for injection to bring to the final total formulation volume (claim 1; page 2, column 3, lines 54-67 to column 4, lines 1-13; and see also Examples). The instant claimed concentration ranges are fully encompassed by or overlap with the ranges disclosed by Weiss.
Weiss teaches a method of making the ophthalmic formulation comprising steps 1-2, mixing cyclosporine into the melted polyoxyl lipid (wherein hydrogenated 40 polyoxyl castor oil melts to a liquid at temperatures >30°C, in which the instant claim 1 temperature of ≥53°C and 33°C are encompassed within); step 3, adding polyalkoxylated alcohol (e.g., octoxynol-40) and mixing to form a uniform homogeneous API solution; step 4, adding the buffer system (e.g., sodium phosphate monobasic, sodium phosphate dibasic) and the tonicity agent (e.g., sodium chloride) to the solution and mixing to achieve a good dissolution; step 5, adding the bioadhesive polymer (e.g., povidone K90) to the solution; step 6, adjusting the pH of the solution if required [with the sodium hydroxide/hydrochloric acid] and making up the final volume with water for injection (claim 4), but also teaches wherein the API mixture can be added to the water for injection, then individually adding excipients sodium phosphate monobasic, sodium phosphate dibasic, and sodium chloride with stirring sufficient to achieve good dissolution of each (page 5, column 9, lines 25-39) or adding and mixing required amount of water for injection to the cyclosporine, polyalkoxylated alcohol and polyoxyl lipid mixture, followed by the adding buffer system and tonicity agent to the solution, then adding the bioadhesive polymer to the solution, followed by adjusting the pH of the solution if required, and making up the final volume with water for injection (page 5, column 10, lines 19-35). The addition of the sodium phosphate monobasic and sodium phosphate dibasic buffering system, the sodium chloride tonicity agent and povidone K90 bioadhesive polymer are listed as being added in that specific order by Weiss, though not explicitly required by Weiss it is logical to do so. In addition, Weiss certainly teaches the preparation of nanomicellar cyclosporine-containing formulations using alternative orders of addition for composition constituents throughout the specification, as exemplified above (see also Example 4). This represents routine optimization of the order of addition disclosed by Weiss.
It would have been prima facie obvious to one of ordinary skill in the art prior to the instant effective filing date to choose the instant claimed concentration ranges and temperatures as they are fully encompassed by or overlap with the ranges disclosed by Weiss, and the order of addition and the specific sequence of adding excipients to the aqueous phase because the optimization of these process parameters would have been routine and obvious to achieving stable micelles based on routine experimentation from the invention of Weiss.
Claim 1 and 2 are rejected under 35 U.S.C. § 103 as being unpatentable over Weiss et al. (US10918694B2; published 16 February 2021, hereinafter referred to as “Weiss”) in view of Takruri (US20200237859A1; published 30 July 2020).
Weiss teaches the limitations of instant claim 1, as described above, from which instant claim 2 depends, however does not explicitly teach mixing the cyclosporine at 200-300 RPM, per the specific limitation of instant claim 2.
Takruri teaches similar cyclosporin aqueous suspension compositions with a pharmaceutically acceptable water-soluble solvent for the cyclosporin, a dispersing agent, a suspending agent and an aqueous vehicle and methods of producing such compositions used to treat ophthalmic disorders (Abstract), wherein Examples 11-40 state “Mixing parameters such as speed of mixing, shear, temperature, etc. are optimized for each composition to yield the desired properties.” (¶[0172]). Thus, the motivation to use the specific instant claimed RPM range of 200-300 is a routine optimization of a basic agitation rate engineering parameter for a mixing step that would have been obvious to a person of skill in the art.
It would have been prima facie obvious to one of ordinary skill in the art prior to the instant effective filing date to add the specific mixing speed limitation to the invention of Weiss with a reasonable expectation of success to make a change, given the teachings of Takrui.
Claim 1, 3 and 4 are rejected under 35 U.S.C. § 103 as being unpatentable over Weiss et al. (US10918694B2; published 16 February 2021, hereinafter referred to as “Weiss”) in view of Weiss (US20190231885A1; published 01 August 2019, hereinafter referred to as “Weiss2”).
Weiss teaches the limitations of instant claim 1, as described above, from which instant claims 3 and 4 depend, however does not explicitly teach a temperature of 35 ±2°C for 40-50 minutes prior to complete dissolution of the cyclosporine and further stirring the mixture for 60 ±5 minutes at the 35°C ±2°C temperature, per the specific limitations of instant claims 3 and 4.
Weiss teaches wherein the hydrogenated 40 polyoxyl castor oil is melted by heating to about 60° C (the instant claim 1 temperature of ≥53°C is encompassed within) and following liquefication the cyclosporine is added and mixed until dissolved, then the octoxynol-40 is added and the entire solution is mixed until uniform then the water for injection is charged into a stainless-steel vessel and stirred until the temperature is 25° C (page 5, column 9, lines 40-49). Further, Example 1 teaches mixed nanomicellar cyclosporine formulations are prepared by melting hydrogenated 40 polyoxyl castor oil, slowly adding cyclosporine thereto, and thereafter substantially homogenizing the ingredients.
Although Weiss does not explicitly teach lowering the temperature of the mixture of cyclosporine with the hydrogenated 40 polyoxyl castor oil to a temperature of 35 ±2°C for 40-50 minutes prior to complete dissolution of the cyclosporine and further stirring the mixture for 60 ±5 minutes at the 35°C ±2°C temperature, the teaching of Weiss in Example 1 provide motivation to mix cyclosporine slowly and substantially mix thereafter. The step of transferring this hot mixture to the water for injection inherently lowers the temperature of the mixture. By optimizing the teachings of Weiss and more precisely and carefully controlling the cooling rate and interrupting dissolution before it is complete, the drug can precipitate to a fine crystalline form with a narrow particle size distribution, wherein the extended stirring at 35°C would then allow the system to stabilize. Stirring for a specific duration of 60 +/-5 minutes specifically at 35°C is a process control parameter that would be conventional to one of skill in the art to optimize dissolution and homogeneity taught by Weiss.
In addition, Weiss2 teaches that adding the active compound to hydrogenated 40 polyoxyl castor oil 40 or 60 at 40° C can be used to entrap active compound. At higher temperatures the hydrogenated polyoxyl castor oil and the drug mixture remain in a viscous liquid state and when allowed to reach room temperature, under natural conditions, the mixture solidifies and develops a waxy solid. This waxy solid when thermostated at 40° C, helps in resuspending the formulation in distilled water to spontaneously develop active compound-containing nanomicells. (¶[0590]), thus the studies show that hydrogenated polyoxyl castor oil can be used to entrap active compound with hot melt method, providing advantages of being an easy and fast method that avoids the use of organic solvent. The waxy solid developed may be helpful in preventing the drug degradation (¶[0595]).
It would have been prima facie obvious to one of ordinary skill in the art prior to the instant effective filing date to add the temperature and time mixing limitations of instant claims 3 and 4 limitation to the invention of Weiss. Mixing until dissolution and lowering the temperature "in 40-50 minutes" is a basic time parameter for a cooling step, readily determined by a person of ordinary skill in the art based on batch size and equipment. In combination with the teaching of Weiss and Weiss2, the instant claimed step of lowering the temperature to 35°C prior to complete dissolution for the instant claimed time periods is a matter of routine experimental optimization variation that is obvious. A person of ordinary skill in the art seeking to optimize the process for stability or handling would find it obvious to adjust this cooling phase temperature and mixing timing as a routine process optimization.
Claims 1, 5, 6, 11 and 12 are rejected under 35 U.S.C. § 103 as being unpatentable over Weiss et al. (US10918694B2; published 16 February 2021, hereinafter referred to as “Weiss”) in view of CEQUA cyclosporine ophthalmic solution FDA labeling information (https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210913s000lbl.pdf; published 2018).
Weiss teaches the limitations of instant claims 1 and 5, as described above, from which instant claims 6, 11 and 12 depend, however does not explicitly the specific osmolality limitations of instant claims 6, 11 and 12.
Weiss teaches embodiments of the formulation with osmolality adjusted to be in the range of about 250-350 mOsmol/kg, however also states more broadly that “…tonicity agents may be used to adjust the osmolality of the compositions.” (page 8, column 15, lines 49-52), and that “…osmolality adjusted in accordance with well-known techniques to proper physiological values.” (page 8, column 15, lines 40-42), wherein a pharmaceutical additive can be added to a composition of the present disclosure to adjust the osmolality of the composition, such as sugars (page 8, column 15, lines 59-66). Evidentiary reference Özalp et al. (Özalp O, Atalay E, Alataş İÖ, Küskü Kiraz Z, Yıldırım N. Assessment of Phosphate and Osmolarity Levels in Chronically Administered Eye Drops. Turk J Ophthalmol. 2019 Jun 27;49(3):123-129), teaches that it was known in the art at the time of the invention that typical eye tears have a normal physiological osmolarity range of 296.5±9.8 mOsm/L (page 2, left column, last 2 lines) and that majority (50%) of immunosuppressant corticosteroid eye drops are hypoosmolar and 71% of all artificial tear formulations (low range 98-287 mOsm/L, see the first paragraph of Materials and Methods on page 2 left column to the first paragraph of the right column; page 3-4, Table 1, and page 5, figure 3). Further, the Discussion section states, “The hyperosmolar state that occurs in dry eye diseases known to trigger the release of inflammatory mediators and proteases, which cause epithelial destruction. Similarly, topical drops with a hyperosmolar character have also been shown to alter tear osmolarity and increase inflammation.” (page 5, right column, paragraph 2), thus providing the motivation to formulate the invention taught by Weiss with a hypotonic osmolality, wherein the specific osmolality range between about 150-200 mOsmol/kg or about 160-190 mOsmol/kg recited in the instant claims would be a matter of obvious routine experimental optimization. Moreover, CEQUA cyclosporine ophthalmic solution FDA labeling information (https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210913s000lbl.pdf; published 2018, accessed 30 December 2025) directly teaches a 0.09 wt % orthorhombic cyclosporine formulation with an osmolality of 160-190 mOsmol/kg and a pH of 6.5-7.2 containing all the same excipients (page 4, figure and first paragraph).
It would have been prima facie obvious to one of ordinary skill in the art prior to the instant effective filing date to add the osmolarity limitations of the instant claims to the invention of Weiss, given it was known in the art at the time of the invention to use this hypotonic osmolality range in the formulation of commercially available CEQUA cyclosporine ophthalmic solution per FDA labeling information.
Claims 1, 5, 7, 9, 10 13, 14, 17 and 18 are rejected under 35 U.S.C. § 103 as being unpatentable over Weiss et al. (US10918694B2; published 16 February 2021, hereinafter referred to as “Weiss”) in view of Gore et al. (US20130023482A1; published 24 January 2013, hereinafter referred to as “Gore”).
Weiss teaches the limitations of instant claims 1 and 5, as described above, from which instant claims 7, 9 and 10 depend, however does not explicitly the specific XRD peak limitations of instant claims 7, 9 and 10.
The limitations of instant claims 13, 14, 17 and 18 are taught as described for instant claim 1 above, excepting the XRD limitations.
Weiss teaches a method designed to produce a clear, nanomicellar solution where cyclosporine is solubilized within surfactant micelles. This process inevitably requires the cyclosporine to be in a solubilized state within the micelles, not as larger crystalline aggregates with some of specific XRD peaks recited in instant claims. The claimed polymorphic state (i.e., amorphous and/or a specific polymorph) would be expected to be a cyclosporine form capable of solubilization and nanomicelle formation via production by the method of Weiss. Identifying these properties does not render the product or process non-obvious. However, Weiss does not explicitly specify the polymorphic state of the cyclosporine (i.e., amorphous or a specific polymorph).
Gore teaches the cyclosporine A (CsA) is known to exist in an amorphous form, liquid crystal form, tetragonal crystalline form (Form 1), an orthorhombic form (Form 3) (¶[0011]; Figure 1) and in dihydrate cyclosporine solvate forms (e.g., cyclosporine A • 2H₂O; ¶[0029]-[0030]), and that the forms can be isolated from one another for use (see claim 1 and 2 only using form 2). Thus, the choice of specific known crystalline cyclosporine A polymorphs (e.g., orthorhombic cyclosporine A form 1 and/or amorphous forms or mixtures thereof) that correspond to a specific characterized X-ray diffraction (XRD) peak 2-theta angles of cyclosporine (¶[0025] and claim 2; Figure 1) and the exclusion of other specific polymorphs or hydrates (e.g., cyclosporine A form 2 and tetragonal form 3 and/or cyclosporine A dihydrate) would be a matter of formulation choice to ensure the desired solubility, stability, and dissolution rate of the drug product. One would be motivated to choose the instant claimed polymorph forms with these peaks providing enhanced stability in an aqueous solution and improved bioavailability (i.e., lower crystallinity amorphous forms can significantly improve the poor water solubility and dissolution rate of cyclosporine to improve absorption- e.g., Neoral® versus Sandimmune®).
It would have been prima facie obvious to one of ordinary skill in the art prior to the instant effective filing date to choose the specific known amorphous form or polymorph form or mixture thereof of cyclosporine in the invention of Weiss, because these forms were known at the time of the invention to be used for the same purpose and are obvious to optimize for achieving stable micelles based on routine experimentation (see In re Aller, 220 F.2d 454 (CCPA 1955)).
Claims 13, 15, 17, 19 and 20 are rejected under 35 U.S.C. § 103 as being unpatentable over Weiss et al. (US10918694B2; published 16 February 2021, hereinafter referred to as “Weiss”) in view of Gore et al. (US20130023482A1; published 24 January 2013, hereinafter referred to as “Gore”) in further view of CEQUA cyclosporine ophthalmic solution FDA labeling information (https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210913s000lbl.pdf; published 2018).
Weiss and Gore teach the limitations of instant claims 13 and 17, as described above, from which instant claims 15, 19 and 20 depend, however does not explicitly teach the specific osmolarity limitations of instant claims 15, 19 and 20.
Weiss teaches embodiments of the formulation with osmolality adjusted to be in the range of about 250-350 mOsmol/kg, however also states more broadly that “…tonicity agents may be used to adjust the osmolality of the compositions.” (page 8, column 15, lines 49-52), and that “…osmolality adjusted in accordance with well-known techniques to proper physiological values.” (page 8, column 15, lines 40-42), wherein a pharmaceutical additive can be added to a composition of the present disclosure to adjust the osmolality of the composition, such as sugars (page 8, column 15, lines 59-66). Evidentiary reference Özalp et al. (Özalp O, Atalay E, Alataş İÖ, Küskü Kiraz Z, Yıldırım N. Assessment of Phosphate and Osmolarity Levels in Chronically Administered Eye Drops. Turk J Ophthalmol. 2019 Jun 27;49(3):123-129), teaches that it was known in the art at the time of the invention that typical eye tears have a normal physiological osmolarity range of 296.5±9.8 mOsm/L (page 2, left column, last 2 lines) and that majority (50%) of immunosuppressant corticosteroid eye drops are hypoosmolar and 71% of all artificial tear formulations (low range 98-287 mOsm/L, see the first paragraph of Materials and Methods on page 2 left column to the first paragraph of the right column; page 3-4, Table 1, and page 5, figure 3). Further, the Discussion section states, “The hyperosmolar state that occurs in dry eye diseases known to trigger the release of inflammatory mediators and proteases, which cause epithelial destruction. Similarly, topical drops with a hyperosmolar character have also been shown to alter tear osmolarity and increase inflammation.” (page 5, right column, paragraph 2), thus providing the motivation to formulate the invention taught by Weiss with a hypotonic osmolality, wherein the specific osmolality range between about 150-200 mOsmol/kg or about 160-190 mOsmol/kg recited in the instant claims would be a matter of obvious routine experimental optimization. Moreover, CEQUA cyclosporine ophthalmic solution FDA labeling information (https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210913s000lbl.pdf; published 2018, accessed 30 December 2025) directly teaches a 0.09 wt % orthorhombic cyclosporine formulation with an osmolality of 160-190 mOsmol/kg and a pH of 6.5-7.2 containing all the same excipients (page 4, figure and first paragraph).
It would have been prima facie obvious to one of ordinary skill in the art prior to the instant effective filing date to add the osmolarity limitations of the instant claims to the invention of Weiss and Gore, given it was known in the art at the time of the invention to use this hypotonic osmolality range in the formulation of commercially available CEQUA cyclosporine ophthalmic solution per FDA labeling information.
Claim Rejections – Nonstatutory 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).
Claims 12-20 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 25-34 of co-pending Application No. 18/683,932 (reference application “’932”). Although the claims at issue are not identical, they are not patentably distinct from each for the reasons outlined below. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The claims of co-pending application ‘932 are directed to stable nanomicellar ophthalmic formulations comprising cyclosporine, hydrogenated polyoxyl castor oil (e.g., hydrogenated castor oil-40), nonionic surfactants such as octoxynol-40, buffering agents, tonicity agents, and polymers such as povidone and methods of preparing such nanomicellar ophthalmic formulations, including heating cyclosporine with a surfactant system, controlled cooling prior to complete dissolution, addition of auxiliary surfactants, buffering salts, tonicity agents, and pH adjustment to ophthalmically acceptable ranges. These claims correspond to the instant claims directed towards methods of making a stable nanomicellar ophthalmic formulation and stable nanomicellar ophthalmic formulations prepared by such methods, wherein the formulations comprise cyclosporine, hydrogenated 40 polyoxyl castor oil, octoxynol-40, phosphate buffers, sodium chloride, povidone, and water for injection, with defined process temperatures, mixing steps, pH ranges, osmolality ranges, and cyclosporine solid-state characteristics.
Claim 30 recites the same limitations of that of instant claim 11, wherein the specification recites, “As used herein in connection with numerical values, the terms “approximately” and “about” mean+/−10% of the indicated value, including the indicated value.” (¶[0271]) and thus also encompasses instant claim 12 and further, the reference application recites, “In a preferred aspect, the osmolality of the formulation is adjusted to between about 160 to about 190 mOsmol/kg.” (¶[0399]). The combination of claims 25, 30, 33 and 34 recite the same limitations as instant claims 13-16. The combination of claims 25, 30, and 31 recite the same limitations as instant claims 17-20.
The claimed stable nanomicellar ophthalmic formulations are prepared by substantially the same processes as those claimed in ‘932, comprise the same essential components in overlapping or identical concentrations and exhibit expected ophthalmic properties such as controlled osmolality and physical stability. The recited osmolality ranges (e.g., 150–200 mOsmol/kg or 160–190 mOsmol/kg) are result-effective variables that would be inherently achieved or readily optimized in the formulations of the reference application.
The limitations directed to amorphous cyclosporine, specific XRD peak patterns, or the absence of alternative crystalline forms merely describe obvious characteristics of cyclosporine when formulation is optimized for stability of nanomicellar systems prepared using the same surfactant-based methods disclosed in ‘932.
Accordingly, the instant claims would improperly extend the right to exclude beyond the term of any patent issuing from ‘932 by claiming obvious variants of the same invention, and therefore constitute nonstatutory double patenting.
These double patenting rejections may be overcome by the filing of a terminal disclaimer in compliance with 37 CFR 1.321, disclaiming any portion of the term of any patent granted on the instant application that would extend beyond the term of any patent issuing from ‘932, and agreeing to maintain common ownership for the life of the patent. Alternatively, Applicant may present arguments establishing that the claims are patentably distinct from the claims of the reference application.
Response to Arguments
Applicant Arguments/Remarks of the reply, filed 06 April 2026, have been fully considered.
The applicant argues that one of ordinary skill in the art would understand that XRD peak positions correspond to crystal lattice spacing and therefore would know how to determine such peaks. That argument does not fully address the written description issue previously raised. The issue is not whether a skilled artisan could generally perform X-ray diffraction. Rather, the issue is whether the originally filed specification reasonably conveys possession of the claimed specific solid-state subject matter, including the precise claimed peak sets, the asserted exclusion of alternative forms, mixed amorphous/crystalline populations, and the breadth of formulations encompassed by the claims.
The specification still does not adequately describe the analytical protocol used to generate the claimed XRD patterns, acceptable instrumental variability or tolerance, how mixed-phase materials are distinguished from trace impurities, and how the “substantially free” limitation is determined analytically in finished micellar formulations. The applicant cites page 19, lines 20-21, asserting “10% or less.” That passage may provide some support for a qualitative definition, but it does not adequately describe how that percentage is measured, whether it is weight %, area %, relative crystallinity %, or diffractogram peak intensity, or how such determination is made in the presence of amorphous cyclosporine and surfactant-containing micellar matrices. Because cyclosporine is known to exhibit polymorphic and partially amorphous behavior, mere recitation of isolated 2-theta values without sufficient structural context does not adequately demonstrate possession of the full scope now claimed.
The applicant asserts that XRD patterns act as a “fingerprint” for crystalline phases. While generally correct, the claims remain indefinite. The claims recite “characteristic XRD peaks” but do not define acceptable instrumental tolerance (e.g., ±0.1° 2θ, ±0.2° 2θ), relative intensity thresholds, peak prominence, whether the recited peaks must all be present as major peaks, whether minor impurity peaks are permitted, how amorphous background is treated, and measurement conditions sufficient to determine claim boundaries with reasonable certainty.
The present claims are not directed merely to identifying known isolated crystalline standards. Rather, the claims cover finished nanomicellar ophthalmic formulations, where surfactants, polymers, and mixed amorphous/crystalline populations may materially affect diffraction profiles. Thus, without objective boundaries, the metes and bounds of the claims remain uncertain.
The applicant’s traversal the § 103 rejections rely heavily on the asserted “surprising and unexpected” discovery that specific temperature conditions (55°C mixing followed by reduction to 35°C prior to complete dissolution) prevent formation of less soluble crystalline forms (forms B and C). However, the applicant has not submitted objective evidence of unexpected results, such as comparative data showing that formulations prepared by the claimed method exhibit superior stability or reduced precipitation compared to formulations prepared by methods within the scope of the prior art (e.g., Weiss with immediate addition to water without reduced-temperature holding). Attorney argument alone cannot overcome a prima facie case of obviousness (See In re De Blauwe, 736 F.2d 699, 705 (Fed. Cir. 1984), wherein attorney argument is not a substitute for evidence).
The applicant argues that the claimed process requires initial mixing at 55°C ± 2°C or above, lowering to 35°C ± 2°C before complete dissolution, resulting in reduced precipitation and reduced formation of certain cyclosporine forms. The argument is not persuasive.
Weiss explicitly teaches that the formulation can be prepared by dissolving cyclosporine in melted hydrogenated 40 polyoxyl castor oil, with the mixture maintained at temperatures sufficient to keep the polyoxyl lipid in liquid form (above its melting point of approximately 30°C). The specific temperatures of 55°C and 35°C are well within the ranges disclosed by Weiss. The step of “lowering the temperature to 35°C ± 2°C prior to complete dissolution” is a routine process control parameter, one of ordinary skill in the art would recognize that controlling the cooling rate and dissolution endpoint is a matter of ordinary optimization, and is not inventive. The claimed temperatures remain result-effective variables. Weiss expressly teaches thermal processing of cyclosporine with hydrogenated polyoxyl castor oil and teaches stability at elevated temperatures. Where the prior art recognizes temperature as affecting formulation behavior, optimization of a workable temperature window constitutes routine experimentation (see In re Aller, 220 F.2d 454 (CCPA 1955). The presently claimed 55°C and 35°C remain conventional formulation-processing temperatures well within the ordinary skill of the art.
The applicant’s assertion of “surprising and unexpected” results is unsupported by comparative data in the record. The specification states that the inventors “surprisingly found” improved stability, but no data comparing the claimed method to a method without the temperature reduction step is provided. Without such data, the finding is merely a statement, not evidence of non-obviousness (see In re Harris, 409 F.3d 1339, 1344 (Fed. Cir. 2005), wherein unexpected results must be established by factual evidence, not mere conclusory statements).
The applicant relies primarily on Example 4. However, the claims broadly cover all formulations within the recited composition ranges, multiple phosphate concentration ranges are permitted, broad pH ranges are claimed in claims 13 and 17, broad process conditions are encompassed, no comparative data demonstrates that the entire claimed scope produces the asserted benefit. Unexpected results must be commensurate in scope with the claims. That burden has not been met.
Furthermore, Example 4 states that the described method can “minimize this precipitation phenomenon”, but does not quantify the degree of minimization or compare to a control. The specification does not demonstrate that the claimed temperature protocol produces a formulation substantially free of forms B and C, while methods without the protocol do not. The alleged polymorphic exclusion is not shown to arise necessarily from the claimed process. The claims do not require analytical confirmation of polymorph content during manufacture, quantitative phase purity, defined cooling rate, defined solvent history, defined crystallization kinetics. Thus, the applicant has not established that the recited process necessarily produces the claimed solid-state outcomes throughout the full claim scope.
The applicant argues that Takruri is directed to aqueous suspensions, not nanomicellar solutions, and therefore does not teach the claimed method. This argument is not persuasive. Takruri is relied upon solely for the general formulation engineering principle that mixing parameters including agitation speed are optimized to obtain desired product properties. The mixing speed limitation (200-300 RPM) is a basic engineering parameter unrelated to whether the final formulation is a suspension or solution. Takruri explicitly teaches optimization of mixing parameters for cyclosporine-containing ophthalmic compositions, providing a direct motivation to optimize the mixing speed in Weiss’s method. Selection of 200-300 RPM is a conventional scale-up process parameter. The fact that Takruri’s compositions are suspensions does not negate its teaching that mixing speed is an optimizable parameter. One of ordinary skill in the art would reasonably expect that the same mixing speed ranges could be applied to Weiss’s method with a reasonable expectation of success.
The applicant argues that Weiss2 does not teach the specific temperature and time parameters. Exact identity is not required. Weiss and Weiss2 collectively teach thermal liquefaction, controlled cooling, entrainment of active ingredient, stabilization through temperature management. Weiss2 teaches the hot melt method for entrapping active compounds in hydrogenated polyoxyl castor oil and the spontaneous formation of nanomicelles upon resuspension. The specific parameters of “40-50 minutes” for cooling and “60 ± 5 minutes” for stirring at 35°C are routine optimization variables. One of ordinary skill in the art seeking to scale up the Weiss process would find it obvious to determine appropriate cooling rates and mixing durations based on batch size, equipment, and desired dissolution characteristics. Selection of cooling time and hold time remains routine process optimization. The applicant has provided no evidence that the specific time parameters are critical (e.g., that 30 minutes or 70 minutes would not work), which is required to establish non-obviousness of a range of routine variables (see In re Aller, 220 F.2d 454, 456 (CCPA 1955), wherein selecting a range from a broader disclosure is prima facie obvious absent evidence of criticality).
The applicant argues that neither Ozalp nor the CEQUA label teach the claimed temperature protocol. This argument misses the point. The rejection does not rely on Ozalp or the CEQUA label to teach the temperature protocol, it relies on Weiss for that teaching. Ozalp and the CEQUA label are cited to supply the osmolality limitation that Weiss lacks. The combination is proper because one of ordinary skill in the art would be motivated to adopt the osmolality of a commercially successful cyclosporine ophthalmic formulation (CEQUA, with osmolality 160-190 mOsmol/kg) into the Weiss formulation, which already contains the same excipients in overlapping concentrations. The fact that the CEQUA label does not disclose the manufacturing method is irrelevant, it discloses the target osmolality, which is an independent variable that can be adjusted in the Weiss method by routine tonicity agent optimization.
The amendments now recite pH 6.5-7.2 in claim 1, osmolality 150-200 and 160-190 mOsmol/kg in claims 6 and 12 and CEQUA expressly teaches 0.09 wt% cyclosporine, substantially the same excipient system, pH 6.5-7.2, and osmolality 160–190 mOsmol/kg. Accordingly, selection of these parameters would have been obvious as routine optimization of known ophthalmic formulation variables. The applicant’s arguments directed to process temperatures do not overcome the combined teachings because Weiss expressly teaches thermal processing and CEQUA supplies the claimed formulation parameters.
The applicant argues that Gore “teaches away” from the claimed invention because Gore describes form B cyclosporine as desirable, while the present claims minimize form B. This argument is unpersuasive. A prior art reference does not teach away merely because it identifies one embodiment as advantageous (see In re Fulton, 391 F.3d 1195 (Fed. Cir. 2004).
Gore teaches the existence of multiple cyclosporine polymorphs (amorphous, tetragonal Form 1, orthorhombic Form 3, dihydrate, etc.) and provides their XRD patterns. The fact that Gore expresses a preference for one form does not teach away from using another form. A reference is said to teach away when a person of ordinary skill in the art, upon reading the reference, would be discouraged from following the path set out in the reference, or would be led in a direction divergent from the path that was taken by the applicant (see In re Kahn, 441 F.3d 977, 990 (Fed. Cir. 2006)). Gore does not state that form B is the only useful form, nor does it criticize or exclude other forms. In fact, Gore explicitly identifies multiple forms and describes methods for preparing them, indicating that the choice of form is a matter of formulation design. Gore broadly teaches multiple known cyclosporine forms and their characterization. Selection among known alternatives remains prima facie obvious.
In addition, the applicant’s own specification acknowledges that the claimed method produces a formulation “substantially free of” forms B and C, but does not demonstrate that the claimed polymorph (form A, with peaks at 6.9, 7.8, 9.4, and 15.9) or the amorphous form is itself novel or non-obvious. One of ordinary skill in the art seeking to formulate a stable cyclosporine solution would be motivated to select a polymorph with high solubility (typically amorphous or a less crystalline form) to enhance dissolution and bioavailability, a well-recognized principle in pharmaceutical formulation. The selection of a known polymorph for a known purpose is obvious (see In re Mayne, 104 F.3d 1339, 1342 (Fed. Cir. 1997), wherein the choice of a known polymorph for its expected properties is prima facie obvious).
Regarding the rejection of claims 13, 15, 17, 19, and 20 over Weiss, Gore, and the CEQUA label, CEQUA teaches an ophthalmic cyclosporine nanomicellar formulation comprising 0.09 wt% cyclosporine, hydrogenated polyoxyl castor oil, octoxynol-40, phosphate buffer, sodium chloride, povidone, pH 6.5–7.2, and osmolality 160–190 mOsmol/kg. Weiss teaches methods of preparing substantially the same nanomicellar ophthalmic compositions using thermal mixing, surfactant dissolution, sequential aqueous addition, pH adjustment, and WFI make-up. Gore teaches known polymorphic and amorphous cyclosporine forms, known XRD-characterized cyclosporine materials, selection of cyclosporine form based on solubility and formulation performance. The combination of Weiss (manufacturing method and formulation), Gore (polymorph teaching), and the CEQUA label (osmolality) renders the claimed invention prima facie obvious.
A person of ordinary skill in the art would have been motivated to use the known CEQUA ophthalmic formulation, prepare it using the known Weiss thermal micellar manufacturing process, select known cyclosporine solid-state forms taught by Gore to optimize dissolution and micellar incorporation. There would have been a reasonable expectation of success because all references concern cyclosporine ophthalmic formulations employing known surfactant-mediated solubilization systems. The applicant has not submitted objective evidence of unexpected results, commercial success, long-felt but unsolved need, or other secondary considerations to rebut this prima facie case.
The applicant requests deferral for the provisional nonstatutory double patenting rejection, however, examination of the present application must proceed on the present record. The claims remain not patentably distinct from the co-pending claims for the reasons previously stated. Accordingly, the provisional nonstatutory obviousness-type double patenting rejection of claims 12-20 is maintained. A terminal disclaimer under 37 CFR 1.321 remains available.
Conclusion
No claims are allowed.
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 (87 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.
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/RL Scotland/
Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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