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 .
Related Inter Partes Review (IPR) proceedings
This application has two related patents with Inter Partes Review (IPR) proceedings:
US Pat. 9,421,199 with two IPR proceedings - IPR2021-00439 (terminated) & IPR2022-00963 (Institution Denied), and
US Pat. 10,842,787 with IPR proceeding - IPR2022-00384 (Final Written Decision).
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 10/31/2025 has been entered.
Claim status
Claims 46-49 and 51-59 are pending and up for examination. Claim 46 was amended to broaden the scope to a composition instead of a solution and to incorporate a pH range stabilized between ~4.5-6.0 for an extended period of time which enhances stability. Therefore, Claims 46-49 and 51-59 are examined on the merits.
Priority
This application is a continuation of 16/677,538, filed November 7, 2019, which is a continuation of U.S. Application No. 15/568,381, filed October 20, 2017, now U.S. Patent No. 10,842,787, which is a § 371 U.S. National Stage Application of International Application No. PCT/US2016/029222, filed April 25, 2016, which is a continuation in part of International Application No. PCT/US2015/037249, filed June 23, 2015, which is a continuation in part of US. Application No. 14/726, 139, filed May 29, 2015, now U.S. Patent No. 9,421,199, issued August 23, 2016, which claims the benefit of U.S. Provisional Application No. 62/151,926, filed April 23, 2015; PCT/OS82613/037249 claims benefit of U.S. Provisional Application No. 62/151,926, filed April 23, 2015; PCT/US2016/029222 claims benefit of U.S. Provisional Application No. 62/151,926, filed April 23, 2015.
Information Disclosure Statement
The Information Disclosure Statement filed 10/31/2025 has been considered by the Examiner. The submission is in compliance with the provisions of 37 CFR §§ 1.97 and 1.98. Enclosed with this Office Action is a return-copy of the Forms PTO-1449 with the Examiner’s signature and indication of those references that have been considered.
Claim Rejections - 35 USC § 103
Response to arguments against the following prior art rejections
Applicant's arguments have been fully considered but have not been found to be persuasive.
Applicant alleges the prior art fails to recognize previously unknown stability problem associated with H2O-based dilute atropine formulations, and thus provides no motivation to arrive at the claimed pH range. However, contrary to applicant’s assertion, optimization of the atropine solution stability problem and its association with pH were expressly recognized in the prior art. In this regard, Kondritzer explicitly teaches evaluation of the stability and degradation of atropine in aqueous solution as a function of pH and temperature and explains that atropine degradation involves acid- and base-catalyzed hydrolysis as outlined in the rejection above. Kondritzer further derived and validated a predictive model identifying the pH at which atropine exhibits maximal stability and reported half-life values across a broad range pH, including values that overlap the claimed pH range of about 4.5-6.0. Clearly, pH-related stability problems were already recognized by others. The fact that Applicant focuses on a lower atropine concentration (about 0.1%) does not establish the existence of an unexpected stability problem.
Applicant argues that the prior art does not explicitly mention degradation of atropine to tropic acid and therefore fails to support the claimed stability language. However, the claims do not require identification of a specific degradation product. For purposes of obviousness, the prior art need only teach how to make a composition having the claimed properties, not identify every degradation pathway or product. Kondritzer teaches that atropine degradation is pH-dependent and identifies pH ranges that minimize degradation. This directly corresponds to the claimed functional result of maintaining atropine stability. Explicit identification of tropic acid is not required.
Applicant cites case law in Example 3 of MPEP 2143(I) to support the argument around discovering previously unknown interaction causing instability (specifically with an omeprazole-containing composition). However, the analogy is not applicable because the present record shows that 1) atropine degradation in aqueous solution was known, 2) pH was known to affect stability, and 3) buffering aqueous pharmaceutical solutions to maintain pH was routine. The claimed invention represents routine optimization of a known formulation parameter, not discovery of a previously unrecognized problem.
Applicant alleges the invention obtains unexpected results, particularly, improved stability within a pH range as claimed. However, the experimental data does not demonstrate unexpected results because the data shows improved stability within a pH range already identified in the prior art as optimal for atropine stability. The data merely confirms a known stability strategy, not an unexpected result.
Rejection maintained and reiterated below
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.
A. Claims 46-49 and 54-59 are rejected under 35 U.S.C. 103 as being unpatentable over Chia et al. (“Atropine for the Treatment of Childhood Myopia: Safety and Efficacy of 0.5%, 0.1%, and 0.01% Doses (Atropine for the Treatment of Myopia 2).” OPHTHALMOLOGY (2012); 119(2): 347−354) in view of Akorn Atropine CareTM ((atropine sulfate ophthalmic solution), NDA 206289 Product Label (Revised July 2014)) and Kondritzer et al. (“Stability of Atropine in Aqueous Solution.” J. AM. PHARM. ASSOC. (1957); 46(9):531−535.)
Independent Claim 46:
A method of treating a myopia in an individual in need thereof, comprising administering to an eye of the individual an effective amount of
a stabilized ophthalmic liquid composition at a pH of about 4.5-6.0 comprising about 0.01 wt% of atropine or atropine sulfate,
water, and
a buffering agent at a pH from about 4.5 to about 6.0,
wherein the buffering agent has a buffer capacity sufficient to maintain the pH of the stabilized ophthalmic composition between about 4.5 to about 6.0 for an extended period of time of at least 1 month arising from the decomposition of atropine to tropic acid, wherein maintaining the pH enhances stability.
Claim 46 Summary/Interpretation:
The sole independent claim recites two elements already known in the art:
(1) [Chia’s] low-concentration atropine formulation for treating myopia, combined with
(2) [Akorn’s] buffering agents to provide an aqueous atropine solution with a pH range that was well known for atropine eyedrop solutions.
Claim 1 further recites the expected result of a stabilized atropine solution with those two elements – namely, maintaining the pH of the solution between about 4.5 to about 6.0 for an extended period of time of at least 1 month that arises from the decomposition of atropine to tropic acid.
Prior art:
Chia discloses the use of low dose solutions comprising 0.01% atropine in eye drops (i.e., liquid) to slow myopia with minimal impact on visual function. See Chia, abstract; p. 347, 353−354. Chia recognized that prior treatments with higher dose 1% atropine eyedrops “were effective in controlling myopic progression,” but caused harmful side effects such as cycloplegia and mydriasis. Id. abstract. To address this, Chia performed experiments in patients using low dose formulations of atropine. “Participants were randomized to receive 0.5%, 0.1%, or 0.01% atropine once nightly in both eyes at an allocation ratio of 2:2:1 in 6 strata defined by gender and age groups of 6 to 7, 8 to 10, and 11 to 12 years, respectively, to ensure gender and age balance across the 3 treatment arms. Trial medications were prepackaged so that bottles were prelabeled with subject number and of similar appearance. Trial medication consisted of the appropriate dose of atropine sulfate with 0.02% of 50% benzalkonium chloride as a preservative.” See p. 348. (Emphasis added.) Chia reported that the lower concentration of “atropine 0.01% has minimal side effects compared with atropine at 0.1% and 0.5%, and retains comparable efficacy in controlling myopia progression.” Id. Based on these results, Chia concluded that “[t]he lowest concentration of 0.01% atropine … is a viable concentration for reducing myopia progression,” and that “the 0.01% formulation exhibited fewer adverse events” than 1%, 0.1%, and 0.5% atropine. Id. at 353-354.
Although Chia discloses the use of 0.01% atropine sulphate and the benzalkonium chloride preservative, Chia is not explicit with teaching the specifically recited buffer systems, the claimed pH range, or the stability profile.
However, one of ordinary skill in the art would have a reasonable expectation of success in buffering the formulation between a pH range of 4.5 to 6.0 because: 1) there are commercially available products that use atropine sulfate and benzalkonium chloride at the claimed pH ranges that are proven to be safe and effective for treating eye conditions; and 2) atropine sulfate is known to be stable at these pH values for long periods of time. For example, see: 1) Akorn; and 2) Kondritzer.
Akorn is the pharmaceutical label of a commercially available atropine sulfate eye drop solution. Akorn discloses an “Atropine Sulfate Ophthalmic Solution, USP 1%” for topical administration to the eye for cycloplegia, mydriasis, and amblyopia. See Akorn, 1st page. Akorn further discloses water and several buffering and stabilizing agents to adjust pH to a range of 3.5-6.0. Id. at 3. These known buffering and stabilizing agents include hydrogen chloride and sodium hydroxide and well-known buffering agents, dibasic sodium phosphate, monobasic sodium phosphate, and edetate disodium. Id. Last, Akorn instructs that administration of the solution should be “1 drop topically to the cul-de-sac of the conjunctiva.” Id. at 1. Akorn’s 1% atropine solution is supplied “in a plastic dropper bottle with a red cap ....” Id. at 5. Thus, Akorn discloses a liquid.
Kondritzer “evaluate[d] the factors involved in the deterioration of aqueous solutions of atropine and its salts” and confirms that degradation of atropine is primarily due to acid- and base-catalyzed hydrolysis. See Kondritzer, 531, 534-5. Kondritzer explains that “[h]ydrolytic reactions catalyzed by both hydrogen and hydroxyl ions, with no detectable water reaction, include hydrolysis of carboxylic esters.” Id. at 532. Kondritzer further discloses that the effects of both the acid- and base-catalyzed reactions are “governed by the hydroxy-ion concentration and the temperature.” Id. at 531. Kondritzer derived an equation to predict the pH at which atropine would be most stable for any hydrogen ion concentration and at any temperature. Id. at 532. Kondritzer found that the experimental results matched those predicted by the theoretical equation. Id. at 534. Based on these data, Kondritzer concludes that, “[a]s expected, the hydrogen ion catalyzed hydrolysis of atropine is slow” and that, “[a]bove pH 4.5, the predominant catalytic reaction involves hydroxyl ion; below pH 3, the predominant catalytic reaction involves hydrogen ion ....” Id. at 534-5. Kondritzer reported in Table III at p. 4 that, at different pH levels at 20oC, the t1/2 in years is:
PNG
media_image1.png
120
1128
media_image1.png
Greyscale
.
One of ordinary skill in the art (POSA) would have found it obvious to treat myopia by administering 0.01% atropine using a known atropine liquid eyedrop solution containing water and a buffer agent for maintaining a pH from about 3.5 to about 6.0 for an extended period of time because Chia discloses the use of eyedrop solution comprising 0.01% atropine for treating myopia and minimizing adverse effects while Akron teaches a prepared eye drop solution of atropine further comprising water and buffering agents (e.g., hydrogen chloride, sodium hydroxide, dibasic sodium phosphate, monobasic sodium phosphate, and edetate disodium) which stabilize pH between 3.5-6.0 while Kondritzer discloses that pH can be adjusted to predictably optimize pH levels wherein the atropine t1/2 in years at the different pH levels of Akron include t1/2 as long as 1800, 811, and 266 years. The artisan would have used the composition with atropine at a concentration of 0.01% to provide efficacy for treating myopia while minimizing adverse effects of higher concentration of atropine. The POSA would have recognized that the presence of the buffering agent of Akron would obtain and maintain the pH range disclosed in Akron and optimize the stability of the atropine in the aqueous composition.
In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. MPEP 2144.05 [R5]. Note, while the prior art does not disclose the exact claimed values, but does overlap, in such instances even a slight overlap in range establishes a prima facie case of obviousness. In re Peterson, 65 USPQ2d 1379, 1382 (Fed. Cir. 2003). Here, Akron teaches buffer agent for maintaining a pH from 3.5-6.0, which overlaps the claimed pH of 4.5-6.0. Therefore, the claimed pH range is rendered obvious. The POSA would have sought to maintain the pH within the range disclosed by Akron for an extended period of time because Kondritzer suggests the pH can be adjusted to optimize atropine composition stability wherein the t1/2 in years at the different pH levels of Akron include t1/2 as long as 1800, 811, and 266 years. The POSA would seek to maintain a stable composition having a stable pH preventing changes in pH due to different factors (heat, tropic acid, other metabolites, etc.) such that the pH is buffered within the disclosed range for as long as possible given that atropine may be administered daily as long as needed (Akron, p. 1).
Claim 47 limits claim 46, wherein the stabilized ophthalmic composition is administered topically. Claim 48 limits claim 46, wherein the stabilized ophthalmic composition is administered by instillation. Akron teaches the composition is topically instilled. See Akron, p. 4.
Claim 49 limits claim 46, wherein the stabilized ophthalmic composition is administered through an eye drop bottle containing the stabilized ophthalmic composition. Chia teaches medication was prepackaged in bottles. See Chia, p. 348. Akorn’s 1% atropine solution is supplied “in a plastic dropper bottle with a red cap ....” See Akron, at p. 5.
Claim 54 limits claim 46, wherein the stabilized ophthalmic composition further comprises an ophthalmically acceptable viscosity agent. Claim 55 limits claim 54, wherein the ophthalmically acceptable viscosity agent comprises hydroxypropylmethyl-cellulose (HPMC). While Chia does not expressly teach a viscosity agent such as hydroxypropylmethyl-cellulose (HPMC), Akron teaches the atropine eyedrop composition comprise hypromellose (i.e., HPMC).
Claim 56 limits claim 46, wherein the stabilized ophthalmic composition further comprises a preservative. Claim 57 limits claim 56, wherein a concentration of the preservative is from about 0.0001% to about 1%. Claim 58 limits claim 56, wherein the preservative is selected from, inter alia, benzalkonium chloride. Chia teaches that the compositions contained 0.02% of 50% benzalkonium chloride as a preservative. See p. 348. Akron teaches the atropine composition contains benzalkonium chloride 0.1 mg (0.01%). See Akron, p. 3. One of ordinary skill in the art would have found it obvious to incorporate benzalkonium chloride 0.1 mg (0.01%) to the composition as a preservative as disclosed by Chia and Akron.
Claim 59 limits claim 46, wherein the stabilized ophthalmic composition is essentially free of procaine and benactyzine, or pharmaceutically acceptable salts thereof. Chia does not require any of these.
B. Claims 52-53 are rejected under 35 U.S.C. 103 as being unpatentable over Chia et al. (cited above) in view of Akorn et al. (cited above) and Kondritzer et al. (cited above), as applied to Claims 46-49 and 54-59 above, taken further in view of Fletcher et al. (“The effect of solution tonicity on the eye.” CLIN. & EXP. OPTOM. (1993); 76.1:17-21.)
Claimed invention
Claim 52 limits claim 46, wherein the stabilized ophthalmic composition further comprises a tonicity adjusting agent. Claim 53 limits claim 52, wherein the tonicity adjusting agent comprises a halide salt of a monovalent cation.
Prior art
While Chia, Akorn and Kondritzer suggests the use of a buffered 0.01% atropine-containing liquid eyedrop solution, their combination does not expressly teach tonicity adjusting agents such as a halide salt of a monovalent cation.
However, it was already known in the art that a tonicity agent is added to ophthalmic formulations to increase adjust osmolarity and aid in comfort for the user. See Fletcher, p. 19.
Fletcher teaches NaCl, a halide salt of a monovalent cation, maintained maximum comfort at a concentration of “0.3 per cent to 2.5 per cent NaCl”. Id.
The POSA would have found it obvious to further incorporate a tonicity agent such as NaCl to the atropine formulation suggested by the prior art in order to optimize and maintain comfort.
C. Claim 51 is rejected under 35 U.S.C. 103 as being unpatentable over Chia et al. (cited above) in view of Akorn et al. (cited above) and Kondritzer et al. (cited above), as applied to Claims 46-49 and 54-59 above, taken further in view of Blumberg et al. (Bull. zur Arzneimittelsicherheit (2013); Nr. 1: 7-12.).
Claimed invention
Claim 51 limits claim 46, wherein the buffering agent comprises an acetate buffering agent, a citrate buffering agent, a carbonate buffering agent, an organic buffering agent, an amino acid buffering agent, or a combination thereof.
Prior art
While Chia, Akorn and Kondritzer suggests the use of a buffered 0.01% atropine-containing liquid eyedrop solution, their combination does not expressly teach the specific buffers claimed (e.g., citrate).
However, it was already known in the art that citrate buffers were used to substitute phosphate buffers. For example, Blumberg teaches that corneal calcifications occur with phosphate‐containing eye products, but not when preparations with citrate buffers are used. See p. 1. Phosphate buffer was replaced with citrate buffer in 2006 after case reports of corneal calcification. Id.
The POSA would have found it obvious to incorporate citrate buffering agent in the atropine compositions suggested by the art in order to provide buffering capacity to the composition while minimizing the potential of causing calcifications of the cornea because Blumberg teaches that corneal calcifications occur with phosphate‐containing eye products, but not when preparations with citrate buffers are used.
Double Patenting
Rejections maintained and reiterated below
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
A. Claims 46-49 and 51-59 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-27 of U.S. Patent No. 9,421,199 B2 in view of Chia et al. (cited above) and Akorn et al. (cited above) and Kondritzer et al. (cited above). Although the claims at issue are not identical, they are not patentably distinct from each other because each claim set discloses a stabilized ophthalmic composition comprising overlapping amounts of atropine or atropine sulfate, water, and a buffering agent such as citrate buffering agent to provide overlapping pH levels to stabilize the composition for extended periods of time, as well as their use in a method of treating a myopia in an individual in need thereof. While the reference claims do not expressly teach 0.1% atropine in the composition, Chia and Akorn teach topical instillation of atropine compositions in a bottle for treating myopia and cycloplegia, respectively (see above), wherein Chia teaches 0.1% atropine solution is effective for treating myopia while minimizing adverse effects and Akorn teaches a known formulation containing atropine, water, HPMC, 0.01% benzalkonium chloride, buffers for stabilizing pH of 4.5-6.0 (see above). The reference composition contains and sodium chloride, a halide salt of a monovalent cation. Kondritzer “evaluate[d] the factors involved in the deterioration of aqueous solutions of atropine and its salts” and derived an equation to predict the pH at which atropine would be most stable for any hydrogen ion concentration and at any temperature. Kondritzer found that the experimental results matched those predicted by the theoretical equation. Kondritzer reported in Table III that at different pH levels at 20oC the t1/2 in years is:
PNG
media_image1.png
120
1128
media_image1.png
Greyscale
.
Thus, the POSA would have found it obvious to use the atropine formulation of the reference claims in combination with a known atropine formulation such as that disclosed by Akorn wherein the amount is adjusted to 0.01% atropine because Chia teaches 0.01% atropine solution for treating myopia while minimizing adverse effects and Akron teaches a known prepared eye drop solution of atropine further comprising water and buffering agents which stabilize pH between 3.5-6.0 while Kondritzer discloses that pH can be adjusted to predictably optimize pH levels wherein the atropine t1/2 in years at the different pH levels of Akron include t1/2 as long as 1800, 811, and 266 years. The artisan would have sought to minimize adverse effects of atropine and maintain a stabilized formulation for an extended period of time.
Response to arguments:
Applicant argues the claim sets are drawn to distinct inventions because deuterated water is taught in the reference claims instead of water as currently claimed. This is not persuasive because the deuterated water is a well--known isotopic variant of water and its use does not impart a nonobvious structural or functional distinction to the claimed atropine formulations in the absence of evidence that deuteration produces a materially different invention.
Applicant’s arguments are not persuasive because they rely on the same distinctions that are addressed above.
B. Claims 46-49 and 51-59 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 9,770,447 B2 in view of Chia et al. (cited above) and Akorn et al. (cited above) and Kondritzer et al. (cited above). Each claim set discloses a stabilized ophthalmic solution comprising overlapping amounts of atropine or atropine sulfate, water, and a buffering agent such as citrate buffering agent to provide overlapping pH levels to stabilize the composition for extended periods of time, as well as their use in a method of treating a myopia in an individual in need thereof. While the reference claims do not expressly teach 0.1% atropine in the composition, Chia and Akorn teach topical instillation of atropine compositions in a bottle for treating myopia and cycloplegia, respectively (see above), wherein Chia teaches 0.1% atropine solution is effective for treating myopia while minimizing adverse effects and Akorn teaches a known formulation containing atropine, water, HPMC, 0.01% benzalkonium chloride, buffers for stabilizing pH of 4.5-6.0 (see above). The reference composition contains and sodium chloride, a halide salt of a monovalent cation. Kondritzer “evaluate[d] the factors involved in the deterioration of aqueous solutions of atropine and its salts” and derived an equation to predict the pH at which atropine would be most stable for any hydrogen ion concentration and at any temperature. Kondritzer found that the experimental results matched those predicted by the theoretical equation. Kondritzer reported in Table III that at different pH levels at 20oC the t1/2 in years is:
PNG
media_image1.png
120
1128
media_image1.png
Greyscale
.
Thus, the POSA would have found it obvious to use the atropine formulation of the reference claims in combination with a known atropine formulation such as that disclosed by Akorn wherein the amount is adjusted to 0.01% atropine because Chia teaches 0.01% atropine solution for treating myopia while minimizing adverse effects and Akron teaches a known prepared eye drop solution of atropine further comprising water and buffering agents which stabilize pH between 3.5-6.0 while Kondritzer discloses that pH can be adjusted to predictably optimize pH levels wherein the atropine t1/2 in years at the different pH levels of Akron include t1/2 as long as 1800, 811, and 266 years. The artisan would have sought to minimize adverse effects of atropine and maintain a stabilized formulation for an extended period of time.
Response to arguments:
Applicant argues the claim sets are drawn to distinct inventions because deuterated water is taught in the reference claims instead of water as currently claimed. This is not persuasive because the deuterated water is a well--known isotopic variant of water and its use does not impart a nonobvious structural or functional distinction to the claimed atropine formulations in the absence of evidence that deuteration produces a materially different invention.
Applicant’s arguments are not persuasive because they rely on the same distinctions that are addressed above.
C. Claims 46-49 and 51-59 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 10,076,515 B2 in view of Chia et al. (cited above) and Akorn et al. (cited above) and Kondritzer et al. (cited above). Each claim set discloses a stabilized ophthalmic composition comprising overlapping amounts of atropine or atropine sulfate, water, and a buffering agent such as citrate buffering agent to provide overlapping pH levels to stabilize the composition for extended periods of time, as well as their use in a method of treating a myopia in an individual in need thereof. While the reference claims do not expressly teach 0.1% atropine in the composition, Chia and Akorn teach topical instillation of atropine compositions for treating myopia and cycloplegia, respectively (see above), wherein Chia teaches 0.1% atropine solution is effective for treating myopia while minimizing adverse effects and Akorn teaches a known formulation containing atropine, water, HPMC, 0.01% benzalkonium chloride, buffers for stabilizing pH of 4.5-6.0 (see above). The reference composition contains and sodium chloride, a halide salt of a monovalent cation. Kondritzer “evaluate[d] the factors involved in the deterioration of aqueous solutions of atropine and its salts” and derived an equation to predict the pH at which atropine would be most stable for any hydrogen ion concentration and at any temperature. Kondritzer found that the experimental results matched those predicted by the theoretical equation. Kondritzer reported in Table III that at different pH levels at 20oC the t1/2 in years is:
PNG
media_image1.png
120
1128
media_image1.png
Greyscale
.
Thus, the POSA would have found it obvious to use the atropine formulation of the reference claims in combination with a known atropine formulation such as that disclosed by Akorn wherein the amount is adjusted to 0.01% atropine because Chia teaches 0.01% atropine solution for treating myopia while minimizing adverse effects and Akron teaches a known prepared eye drop solution of atropine further comprising water and buffering agents which stabilize pH between 3.5-6.0 while Kondritzer discloses that pH can be adjusted to predictably optimize pH levels wherein the atropine t1/2 in years at the different pH levels of Akron include t1/2 as long as 1800, 811, and 266 years. The artisan would have sought to minimize adverse effects of atropine and maintain a stabilized formulation for an extended period of time.
Response to arguments:
Applicant argues the claim sets are drawn to distinct inventions because deuterated water is taught in the reference claims instead of water as currently claimed. This is not persuasive because the deuterated water is a well--known isotopic variant of water and its use does not impart a nonobvious structural or functional distinction to the claimed atropine formulations in the absence of evidence that deuteration produces a materially different invention.
Applicant’s arguments are not persuasive because they rely on the same distinctions that are addressed above.
D. Claims 46-49, 51 and 54-59 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 10,201,534 B2 in view of Chia et al. (cited above) and Akorn et al. (cited above) and Kondritzer et al. (cited above). Each claim set discloses a stabilized ophthalmic composition comprising overlapping amounts of atropine or atropine sulfate, water, and a buffering agent such as citrate buffering agent to provide overlapping pH levels to stabilize the composition for extended periods of time, as well as their use in a method of treating a myopia in an individual in need thereof. While the reference claims do not expressly teach 0.1% atropine in the composition, Chia and Akorn teach topical instillation of atropine compositions in a bottle for treating myopia and cycloplegia, respectively (see above), wherein Chia teaches 0.1% atropine solution is effective for treating myopia while minimizing adverse effects and Akorn teaches a known formulation containing atropine, water, HPMC, 0.01% benzalkonium chloride, buffers for stabilizing pH of 4.5-6.0 (see above). Kondritzer “evaluate[d] the factors involved in the deterioration of aqueous solutions of atropine and its salts” and derived an equation to predict the pH at which atropine would be most stable for any hydrogen ion concentration and at any temperature. Kondritzer found that the experimental results matched those predicted by the theoretical equation. Kondritzer reported in Table III that at different pH levels at 20oC the t1/2 in years is:
PNG
media_image1.png
120
1128
media_image1.png
Greyscale
.
Thus, the POSA would have found it obvious to use the atropine formulation of the reference claims in combination with a known atropine formulation such as that disclosed by Akorn wherein the amount is adjusted to 0.01% atropine because Chia teaches 0.01% atropine solution for treating myopia while minimizing adverse effects and Akron teaches a known prepared eye drop solution of atropine further comprising water and buffering agents which stabilize pH between 3.5-6.0 while Kondritzer discloses that pH can be adjusted to predictably optimize pH levels wherein the atropine t1/2 in years at the different pH levels of Akron include t1/2 as long as 1800, 811, and 266 years. The artisan would have sought to minimize adverse effects of atropine and maintain a stabilized formulation for an extended period of time.
Response to arguments:
Applicant argues the claim sets are drawn to distinct inventions because deuterated water is taught in the reference claims instead of water as currently claimed. This is not persuasive because the deuterated water is a well--known isotopic variant of water and its use does not impart a nonobvious structural or functional distinction to the claimed atropine formulations in the absence of evidence that deuteration produces a materially different invention.
Applicant’s arguments are not persuasive because they rely on the same distinctions that are addressed above.
E. Claims 52-53 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 10,201,534 B2 in view of Chia et al. (cited above) and Akorn et al. (cited above) and Kondritzer et al. (cited above), as applied to Claims 46-49, 51, 54-59 above, taken further in view of Fletcher et al. (“The effect of solution tonicity on the eye.” CLIN. & EXP. OPTOM. (1993); 76.1:17-21.)
Claim 52 limits claim 46, wherein the stabilized ophthalmic composition further comprises a tonicity adjusting agent. Claim 53 limits claim 52, wherein the tonicity adjusting agent comprises a halide salt of a monovalent cation. While the reference claims suggests the use of a buffered 0.01% atropine-containing liquid eyedrop solution, their combination does not expressly teach tonicity adjusting agents such as a halide salt of a monovalent cation. However, it was already known in the art that a tonicity agent is added to ophthalmic formulations to adjust osmolarity and aid in comfort for the user. See Fletcher, p. 19. Fletcher teaches NaCl, a halide salt of a monovalent cation, maintained maximum comfort at a concentration of “0.3 per cent to 2.5 per cent NaCl”. Id. The POSA would have found it obvious to further incorporate a tonicity agent such as NaCl to the atropine formulation suggested by the reference claims in order to optimize and maintain comfort.
Response to arguments:
Applicant’s arguments are not persuasive for the same reasons provided for rejection D above.
F. Claims 46-49 and 51-59 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-32 of U.S. Patent No. 10,864,208 B2 in view of Chia et al. (cited above) and Akorn et al. (cited above) and Kondritzer et al. (cited above). Each claim set discloses a stabilized ophthalmic composition comprising overlapping amounts of atropine or atropine sulfate, water, a metal halide salt of a monovalent cation (sodium chloride), and a buffering agent such as a citrate buffering agent to provide overlapping pH levels to stabilize the composition for extended periods of time. While the reference claims do not expressly teach 0.1% atropine in the composition, Chia and Akorn teach topical instillation of atropine compositions in a bottle for treating myopia and cycloplegia, respectively (see above), wherein Chia teaches 0.1% atropine solution is effective for treating myopia while minimizing adverse effects and Akorn teaches a known formulation containing atropine, water, HPMC, 0.01% benzalkonium chloride, buffers for stabilizing pH of 4.5-6.0 (see above). Kondritzer “evaluate[d] the factors involved in the deterioration of aqueous solutions of atropine and its salts” and derived an equation to predict the pH at which atropine would be most stable for any hydrogen ion concentration and at any temperature. Kondritzer found that the experimental results matched those predicted by the theoretical equation. Kondritzer reported in Table III that at different pH levels at 20oC the t1/2 in years is:
PNG
media_image1.png
120
1128
media_image1.png
Greyscale
.
Thus, the POSA would have found it obvious to use the atropine formulation of the reference claims in combination with a known atropine formulation such as that disclosed by Akorn wherein the amount is adjusted to 0.01% atropine because Chia teaches 0.01% atropine solution for treating myopia while minimizing adverse effects and Akron teaches a known prepared eye drop solution of atropine further comprising water and buffering agents which stabilize pH between 3.5-6.0 while Kondritzer discloses that pH can be adjusted to predictably optimize pH levels wherein the atropine t1/2 in years at the different pH levels of Akron include t1/2 as long as 1800, 811, and 266 years. The artisan would have sought to minimize adverse effects of atropine and maintain a stabilized formulation for an extended period of time.
Response to arguments:
Applicant argues the claim sets are drawn to distinct inventions because deuterated water is taught in the reference claims instead of water as currently claimed. This is not persuasive because the deuterated water is a well--known isotopic variant of water and its use does not impart a nonobvious structural or functional distinction to the claimed atropine formulations in the absence of evidence that deuteration produces a materially different invention.
Applicant’s arguments are not persuasive because they rely on the same distinctions that are addressed above.
G. Claims 46-49 and 51-59 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11,596,625 B2 in view of Chia et al. (cited above) and Akorn et al. (cited above) and Kondritzer et al. (cited above). Each claim set discloses a stabilized ophthalmic composition comprising overlapping amounts of atropine or atropine sulfate, water, a metal halide salt of a monovalent cation (sodium chloride), and a buffering agent such as a citrate buffering agent to provide overlapping pH levels to stabilize the composition for extended periods of time. While the reference claims do not expressly teach 0.1% atropine in the composition, Chia and Akorn teach topical instillation of atropine compositions in a bottle for treating myopia and cycloplegia, respectively (see above), wherein Chia teaches 0.1% atropine solution is effective for treating myopia while minimizing adverse effects and Akorn teaches a known formulation containing atropine, water, HPMC, 0.01% benzalkonium chloride, buffers for stabilizing pH of 4.5-6.0 (see above). Kondritzer “evaluate[d] the factors involved in the deterioration of aqueous solutions of atropine and its salts” and derived an equation to predict the pH at which atropine would be most stable for any hydrogen ion concentration and at any temperature. Kondritzer found that the experimental results matched those predicted by the theoretical equation. Kondritzer reported in Table III that at different pH levels at 20oC the t1/2 in years is:
PNG
media_image1.png
120
1128
media_image1.png
Greyscale
.
Thus, the POSA would have found it obvious to use the atropine formulation of the reference claims in combination with a known atropine formulation such as that disclosed by Akorn wherein the amount is adjusted to 0.01% atropine because Chia teaches 0.01% atropine solution for treating myopia while minimizing adverse effects and Akron teaches a known prepared eye drop solution of atropine further comprising water and buffering agents which stabilize pH between 3.5-6.0 while Kondritzer discloses that pH can be adjusted to predictably optimize pH levels wherein the atropine t1/2 in years at the different pH levels of Akron include t1/2 as long as 1800, 811, and 266 years. The artisan would have sought to minimize adverse effects of atropine and maintain a stabilized formulation for an extended period of time.
Response to arguments:
Applicant argues the claim sets are drawn to distinct inventions because deuterated water is taught in the reference claims instead of water as currently claimed. This is not persuasive because the deuterated water is a well--known isotopic variant of water and its use does not impart a nonobvious structural or functional distinction to the claimed atropine formulations in the absence of evidence that deuteration produces a materially different invention.
Applicant’s arguments are not persuasive because they rely on the same distinctions that are addressed above.
H. Claims 46-49 and 51-59 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11,883,390 B2 in view of Chia et al. (cited above) and Akorn et al. (cited above) and Kondritzer et al. (cited above). Each claim set discloses a stabilized ophthalmic composition comprising overlapping amounts of atropine or atropine sulfate, water, a metal halide salt of a monovalent cation, and a buffering agent such as a citrate buffering agent to provide overlapping pH levels to stabilize the composition for extended periods of time. They also teach the use of the composition for treating myopia. While the reference claims do not expressly teach 0.1% atropine in the composition, Chia and Akorn teach topical instillation of atropine compositions in a bottle for treating myopia and cycloplegia, respectively (see above), wherein Chia teaches 0.1% atropine solution is effective for treating myopia while minimizing adverse effects and Akorn teaches a known formulation containing atropine, water, HPMC, 0.01% benzalkonium chloride, buffers for stabilizing pH of 4.5-6.0 (see above). Kondritzer “evaluate[d] the factors involved in the deterioration of aqueous solutions of atropine and its salts” and derived an equation to predict the pH at which atropine would be most stable for any hydrogen ion concentration and at any temperature. Kondritzer found that the experimental results matched those predicted by the theoretical equation. Kondritzer reported in Table III that at different pH levels at 20oC the t1/2 in years is:
PNG
media_image1.png
120
1128
media_image1.png
Greyscale
.
Thus, the POSA would have found it obvious to use the atropine formulation of the reference claims in combination with a known atropine formulation such as that disclosed by Akorn wherein the amount is adjusted to 0.01% atropine because Chia teaches 0.01% atropine solution for treating myopia while minimizing adverse effects and Akron teaches a known prepared eye drop solution of atropine further comprising water and buffering agents which stabilize pH between 3.5-6.0 while Kondritzer discloses that pH can be adjusted to predictably optimize pH levels wherein the atropine t1/2 in years at the different pH levels of Akron include t1/2 as long as 1800, 811, and 266 years. The artisan would have sought to minimize adverse effects of atropine and maintain a stabilized formulation for an extended period of time.
Response to arguments:
Applicant argues the claim sets are drawn to distinct inventions because deuterated water is taught in the reference claims instead of water as currently claimed. This is not persuasive because the deuterated water is a well--known isotopic variant of water and its use does not impart a nonobvious structural or functional distinction to the claimed atropine formulations in the absence of evidence that deuteration produces a materially different invention.
Applicant’s arguments are not persuasive because they rely on the same distinctions that are addressed above.
I. Claims 46-49 and 51-59 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11,890,277 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because each claim set discloses a stabilized ophthalmic composition comprising about 0.01 wt% of atropine or atropine sulfate, water, and a buffering agent such as citrate buffering agent to provide overlapping pH levels to stabilize the composition for extended periods of time, as well as their use in a method of treating a myopia in an individual in need thereof by topical instillation. The composition contains benzalkonium chloride, HPMC, halide salt of a monovalent cation and is stored in bottles.
Response to arguments:
Applicant argues the claim sets are drawn to distinct inventions because deuterated water is taught in the reference claims instead of water as currently claimed. This is not persuasive because the deuterated water is a well--known isotopic variant of water and its use does not impart a nonobvious structural or functional distinction to the claimed atropine formulations in the absence of evidence that deuteration produces a materially different invention.
Applicant’s arguments are not persuasive because they rely on the same distinctions that are addressed above.
J. Claims 46-49 and 51-59 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11,896,588 B2 Although the claims at issue are not identical, they are not patentably distinct from each other because each claim set discloses a stabilized ophthalmic composition comprising about 0.01 wt% of atropine or atropine sulfate, water, and a buffering agent such as citrate buffering agent to provide overlapping pH levels to stabilize the composition for extended periods of time, as well as their use in a method of treating a myopia in an individual in need thereof by topical instillation. The composition contains benzalkonium chloride, HPMC, halide salt of a monovalent cation and is stored in bottles.
Response to arguments:
Applicant argues the claim sets are drawn to distinct inventions because deuterated water is taught in the reference claims instead of water as currently claimed. This is not persuasive because the deuterated water is a well--known isotopic variant of water and its use does not impart a nonobvious structural or functional distinction to the claimed atropine formulations in the absence of evidence that deuteration produces a materially different invention.
Applicant’s arguments are not persuasive because they rely on the same distinctions that are addressed above.
Terminal Disclaimer
The terminal disclaimer filed on 10/31/2025 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration dates of United States Patent Numbers: 10,842,787, 11,382,909, 10,813,923, 10,888,557, 10,940,145, and 10,953,002 has been reviewed and is accepted. The terminal disclaimer has been recorded.
Conclusion
No claims are allowed.
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 CHRIS E SIMMONS whose telephone number is (571)272-9065. The examiner can normally be reached M-F: 9:30-6:00p.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James H. Alstrum-Acevedo can be reached on (571) 272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/CHRIS E SIMMONS/Examiner, Art Unit 1629
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622