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 .
Priority
The present Application is a continuation of U.S. Application No. 16/677,538, filed November 7, 2019, which is a continuation of U.S. Application No. 15/568,381, filed October 20, 2017, 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 both International Application No. PCT/US2015/037249, filed June 23, 2015, and of U.S. Application No. 14/726,139, filed May 29, 2015 (now U.S. Patent No. 9,421,199, issued August 23, 2016). International Application No. PCT/US2015/037249 is also a continuation-in-part of U.S. Application No. 14/726,139 (now U.S. Patent No. 9,421,199), which claims the benefit of U.S. Provisional Application No. 62/151,926, filed April 23, 2015. The Examiner thanks Applicant’s representative for pointing out the chain of priority as indicated in the corrected Application Data Sheet filed June 23, 2020 and as reflected in the updated filing receipt of June 29, 2020.
Status of the Claims
In the amendment filed September 29, 2025, claim 57 is canceled and claim 48 is amended. Claims 1-47 were previously canceled. Claims 48-56 and 58-59 are currently pending and subject to examination herein.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on September 29, 2025 is acknowledged.
Previous Rejections and/or Objections
Any objections and/or rejections raised in the previous Office Action but not reiterated below are considered to have been withdrawn.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 48-50, 52-53, 56, and 58 are obvious over Akorn, Kumar, Cooper, and Fang:
Claims 48-50, 52-53, 56, and 58 are rejected under 35 U.S.C. 103 as being unpatentable over the non-patent publication FDA Drug Label Archive for Atropine Sulfate Solution, NDC code 17478-215-02, first published in 2010 (hereinafter, “Akorn”), in view of the non-patent publication, Recent Challenges and Advances in Ophthalmic Drug Delivery System, The Pharma Innov., 1, pgs. 1-15 (2012) by Kumar et al. (hereinafter, “Kumar”), further in view of the non-patent publication, Maximum Atropine Dose Without Clinical Signs or Symptoms, Optom. & Vision Sci., 90, pgs. 1467-1472 (2013) by Cooper et al. (hereinafter, “Cooper”), and further still in view of the non-patent publication, Prevention of Myopia Onset with 0.025% Atropine in Premyopic Children, J. Ocul. Pharmacol. Ther., 26, pgs. 341-345 (2010), by Fang et al. (hereinafter, “Fang”). Akorn was obtained from the DailyMed website at the url dailymed.nlm.nih.gov/dailymed/getArchivalFile.cfm?archive_id=25609, and a consolidated copy of the 2010 version (including label and box on pg. 1 and description on pgs. 2-3) is appended to this Office Action.
It is noted that the present amendment has incorporated the feature of previous claim 57 into claim 48, so that present claim 48 is identical in scope to previous claim 57. This involved amending claim 48 to further include a citrate buffer, in addition to the elements previously recited. With respect to the previous rejection of claim 57, Applicant argues first that the cited references fail to provide a motivation or a reasonable expectation of success for one of ordinary skill in the art to modify the cited references to arrive at the claimed combination (pg. 5, 3rd paragraph through pg. 6, 1st paragraph of Applicant’s Remarks of September 29, 2025). To this point, Applicant notes that Akorn teaches a phosphate buffer, Kumar teaches a citrate buffer, Cooper and Fang are silent as to buffer, and none of the references teach a combination of buffers. This argument is fully considered, but is not found persuasive.
The present case, on the current record is one where “[t]he combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398 (2007). Similarly, “improvement is more than the predictable use of prior art elements according to their established functions.” KSR. In the present case, phosphate buffer and citrate buffer are both being used, according to known methods, to buffer an ophthalmic solution, as is conventional for each of these buffers in this capacity. Furthermore, according to the present record, the two buffers are used in this combination to yield predictable results – buffering of the ophthalmic solution. A finding of obviousness is consistent with KSR, and goes to the question of motivation and expectation of success. One would be motivated to use these two buffers for the same reason one would be motivated to use either of them; to buffer the ophthalmic solution, according to their established functions.
Applicant further reiterates an argument, similar to a previous argument made in Applicant’s response of June 28, 2024 to the Non-Final Office Action of April 2, 2024, that one would not have had a reasonable expectation of success in using citrate and phosphate buffer, at least in part because Kumar states “the limited buffer capacity of the lachrymal fluid precludes the use of strong buffers outside the pH range of 6.8-7.6.” As noted in the Final Office Action of September 10, 2024, buffer strength, or capacity, is a function of pKa and of buffer concentration. See, for example, the non-patent publication, Buffer Capacity – an underestimated parameter in prep RP-HPLC, Kromasil web page, (2011) by Kromasil (hereinafter, “Kromasil”), obtained at the url https://www.kromasil.com/notes/?NOTEhexl (2011), stating that buffer capacity is a function of pH, concentration, and pKa of the weak acid (i.e. a function of (i) the difference between pH and pKa, and (ii) buffer concentration), second paragraph). Thus, regardless of the buffer identity or pKa, one could avoid an overly “strong” buffer by utilizing the buffer at low concentration. Thus, while Kumar did not specify exactly what it meant by “strong buffers,” presumably Kumar intended to avoid buffer compositions of high capacity that would be unable to rapidly equilibrate to physiological pH when administered. This issue could readily be avoided by using a low concentration buffer, regardless of its identity or pKa. In any event, Kumar plainly does not preclude the use of citrate buffer in ophthalmic solutions, as it expressly discloses this use, and Akron expressly discloses phosphate buffer in ophthalmic atropine solutions. Nothing in either reference or in the art of record suggests there would be any problem with combining them.
Furthermore, and insofar as it may be suggested that it is nonobvious to combine individual buffers into a two-buffer system, when the individual buffers themselves are known, it can be noted that such combination of individually-known buffers into buffer systems in ophthalmic solutions is known. See, for example, International Patent Application No. WO1993/018764 to Giovanoni (hereinafter, “Giovanoni”). Giovanoni teaches an ophthalmic solution having a “plurality of buffers” that are differentiated from each other in their buffering capability (pg. 7, lines 12-16). Giovanoni further teaches that the “plurality of buffers can include phosphate and citrate buffers (pg. 19, lines 25-27). While not expressly cited herein as prior art, because it is not needed, Giovanoni demonstrates that, consistent with KSR, it is not new to combine the individually known buffers and use them, in combination, according to their standard usage as buffers.
Applicant next asserts that the combination of phosphate and citrate buffers provide “unexpected benefits,” (pg. 6, 3rd-5th paragraphs of Applicant’s Remarks). To this point, Applicant quotes a paragraph from International Patent Application Publication No. WO2017/204262 to Tan et al. (hereinafter, “Tan”). It is noted that Tan was listed in the IDS filed September 8, 2023. While not expressly stated in Applicant’s Remarks, it is believed that Applicant intends to argue that, even if the prima facie case of obviousness is valid, the prima facie case is rebutted by objective evidence of nonobviousness, unexpected results in the present case, as indicated by Tan. This argument has been preliminarily considered, and is found insufficient.
As a first matter, it is noted that Applicant has mischaracterized Tam when Applicant states that, “8 different formulations of 0.01% atropine with a pH of 43 were tested to determine the amount of mydriatic acid under different buffer concentrations,” (emphasis added). This likely was a typographical error, but Tan evaluates the degree of mydriatic action (i.e. pupillary dilation) under various conditions, not mydriatic acid.
Further, Applicant has not made a complete argument, establishing a nexus between the evidence in Tam and the claimed invention. For example, Applicant should discuss specifically what Tam teaches with respect to buffer and mydriatic action, how this teaching is consistent with the claimed invention including its scope, and preferably why the allegedly unexpected result is something to be desired. All of these things should be stated plainly on the record, rather than left to inference.
Finally, while full consideration of the apparent argument of objective evidence of nonobviousness in the form of unexpected results awaits entry of a complete argument, it may be observed that Tam appears to provide evidence of reduced mydriasis when citrate is added under a specific set of circumstances (e.g. particular pH, particular phosphate concentration). Without fully considering the evidence because a complete argument hasn’t been presented, it may be wondered, for example, (i) whether the apparent effect is due to the combination of citrate with phosphate, or merely due to increased overall buffer concentration, and (ii) whether the effect cited when pH is 4.3 and NaH2PO4 is present at 1 mg/mL is applicable to other pHs, concentrations, and conditions generally within the scope of claim 48.
The rejections, as modified in view of the amendments, are maintained in substance.
Modified, but substantially reiterated rejections:
Claim 48 recites an ophthalmic composition comprising atropine sulfate at a concentration from 0.001 wt% to 0.05 wt%, water, a phosphate buffer, a citrate buffer, and a water-soluble polymer, wherein the water-soluble polymer is selected from the group consisting of a cellulose derivative, a carboxyvinyl polymer, and combinations thereof, and wherein the ophthalmic composition
Akorn teaches an aqueous solution (an ophthalmic composition) containing atropine sulfate and water (pg. 2, lines 5-7, describing atropine sulfate as sole active ingredient; and pg. 2 lines 9-11 describing purified water as the only solvent). Akorn teaches that the solution contains dibasic/monobasic sodium phosphate (i.e. a phosphate buffer) and can have hydrochloric acid and/or sodium hydroxide added to adjust pH to a pH within a range of from 3.5 to 6.0 (i.e. a pH of 6 or lower; pg. 2, lines 9-11). Akorn further teaches, at pg. 2, line 9 that the solution contains Hypromellose (i.e. hydroxypropyl methylcellulose, a cellulose derivative).
Akorn teaches use of a phosphate buffer but does not expressly teach use of a citrate buffer in the ophthalmic solution. It would have been obvious to one of ordinary skill in the art to use such a buffer system, however, as citrate was well-known in the art as safe and effective for ophthalmic solutions. See, for example, Kumar.
Kumar teaches that citrate is a commonly used buffer in the context of ophthalmic solutions (pg. 5, third paragraph). And while Kumar teaches that citrate would be undesirable in a formulation intended to be at a pH of about 7.4, due to poor buffering capacity at this pH, citrate would be highly effective within the pH range recited in claim 48, as citrate has pKa’s across this range. It thus would have been obvious to replace or supplement the phosphate buffer of Akorn with the commonly used citrate buffer as taught by Kumar.
Akorn teaches the atropine sulfate in the composition is at 1%, and does not explicitly teach an atropine sulfate concentration from 0.001 wt % to 0.05 wt %, nor does Kumar teach this. It would have been obvious to one of ordinary skill to utilize an atropine sulfate concentration within this range, however, because atropine sulfate concentrations in this range were well-known in the art to be effective and to have fewer undesirable side effects than are observed with higher concentrations such as the 1% of Akorn. See, for example, Cooper and Fang.
Cooper teaches a clinical trial of atropine at different concentrations to determine the highest concentration that does not result in significant symptoms from pupillary dilation and accommodative paralysis (Abstract, Purpose). Cooper further teaches that 0.02% atropine is the highest concentration that does not produce significant clinical symptoms from accommodation paralysis or pupillary dilation (Abstract, Conclusions).
Fang teaches a retrospective study on the effectiveness of 0.025% atropine eye drops to prevent myopia onset in children (Abstract). Fang teaches that, as part of the study, premyopic children were given 0.025% atropine sulphate (pg. 342, first and second full paragraphs) nightly during the course of treatment. Fang reports that the 0.025% atropine sulphate/sulfate was effective at preventing diopter shift in the children who received it, relative to a control group (Abstract, Results). Fang thus concludes that 0.025% atropine sulfate can prevent myopia onset and myopic shift in premyopic schoolchildren for a 1-year period.
It would have been obvious to modify the ophthalmic composition of Akorn and Kumar by using the much lower atropine concentration (0.02% or 0.025%), at least for preventing myopia onset in children as taught by Fang, and to avoid side effects such as accommodation paralysis or pupillary dilation as taught by Cooper.
With respect to claim 49, Fang teaches the concentration of 0.025 wt % atropine sulfate is effective for prevention of myopia onset. With respect to claims 50 and 52, Akorn teaches, at pg. 2, line 9, that the composition includes Hypromellose (i.e. hydroxypropyl methylcellulose, a cellulose derivative). With respect to claim 53, the monobasic and dibasic sodium phosphate of Akorn also constitute a “tonicity agent” of the instant claims (see paragraph [0021] of the instant specification, defining “tonicity adjusting agents”). With respect to claim 56, Akorn teaches the solution is to be administered “topically to the eye(s),” (pg. 3, lines 15-16). As such, it is suitable for topical administration. With respect to claim 58, Akorn teaches that the composition includes benzalkonium chloride (pg. 2, line 9)
Claim 51 is obvious over Akorn, Kumar, Cooper, Fang, and Almeida:
Claim 51 is rejected under 35 U.S.C. 103 as being unpatentable over Akorn, in view of Kumar, Cooper and Fang, and further in view of the non-patent publication, In situ gelling systems: a strategy to improve the bioavailability of ophthalmic pharmaceutical formulations, Drug Discover Today, 19, pgs. 400-412 (2014) by Almeida et al. (hereinafter, “Almeida”).
Claim 51 recites that the water soluble polymer is a carboxyvinyl polymer (i.e. the composition contains a carboxyvinyl polymer rather than a cellulose derivative. Akorn, Kumar, Cooper, and Fang are applied to claim 51 as to claim 48 above, but none of them explicitly teaches that the composition includes a carboxyvinyl polymer. It would have been obvious, however, to incorporate a carboxyvinyl polymer into the composition of Akorn, because carboxyvinyl polymer was known in the art as being, like the HPMC of Akorn, a useful gelling agent in eye drops.
Almeida teaches addition biocompatible polymers in ophthalmic solutions is effective to increase the bioavailability of the ophthalmic drugs (Abstract). Almeida further teaches that certain polymer increase the viscosity and mucoadhesive properties of the formulations (pg. 403, right column, third paragraph), and that the most common bioadhesive polymers used in ophthalmic formulations include cellulose derivatives (like the HPMC of Akorn) and carboxyvinyl polymers (pg. 403, right column, fourth paragraph). It thus would have been obvious to replace or supplement the viscosity agent HPMC of Akorn with a comparable carboxyvinyl polymer as taught by Almeida.
Claims 54-55 are obvious over Akorn, Kumar, Cooper, Fang, and Tavlarakis:
Claims 54-55 are rejected under 35 U.S.C. 103 as being unpatentable over Akorn, in view of Kumar, Cooper and Fang, and further in view of the non-patent publication, Chemical Analysis of Ophthalmic Solutions, Seton Hall University Dissertations & Theses, pgs. 1-155 (2013) by Tavlarakis (hereinafter, “Tavlarakis”).
Claim 54 recites that the tonicity agent is one selected from a group that includes glycerin, and claim 55 recites that the tonicity agent is glycerin. Akorn, Kumar, Cooper, and Fang are applied to claims 54 and 55 as to claim 48, above, but none explicitly teaches glycerin as a tonicity agent. It would have been obvious to include glycerin in the composition of Akorn, Kumar, Cooper, and Fang, however, because glycerin was well-known in the art as a common tonicity adjusting agent in ophthalmic solutions, and was also known to have additional benefits. See, for example, Tavlarakis.
Tavlarakis teaches a study of the composition of various ophthalmic solutions (Abstract), and teaches that glycerin is a common ingredient used for tonicity adjustment of ophthalmic solutions, in addition to various common salts and sugars (pg. 9, first full sentence). Tavlarakis further teaches that glycerin is a common lubricant, or demulcent, in ophthalmic solutions, that controls viscosity and offers pain relief to irritated mucous membranes (pg. 9, first full paragraph). It thus would have been obvious to include glycerin as a tonicity adjusting agent in the ophthalmic solution of Akorn, Kumar, Cooper, and Fang for the purpose of controlling tonicity, but also controlling viscosity and offering pain relief in case the ocular membrane is irritated, as taught by Tavlarakis.
Claim 59 is obvious over Akorn, Kumar, Cooper, Fang, and Ushio:
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Akorn, Kumar, Cooper, and Fang, and further in view of U.S. Patent No. 5,185,372 to Ushio et al (hereinafter, “Ushio”).
Claim 59 recites that the composition further comprises [Symbol font/0x65]-aminocaproic acid, presumably as a buffer, since the only mention of [Symbol font/0x65]-aminocaproic acid in the specification is that it can be used as a buffer (paragraph [00136]). Akorn, Kumar, Cooper, and Fang are applied to claim 59 as to claim 48, above, but none explicitly teaches use of [Symbol font/0x65]-aminocaproic acid. It would have been obvious to include [Symbol font/0x65]-aminocaproic acid as a buffer in the ophthalmic solution of Akorn, Kumar, Cooper, and Fang, however, because [Symbol font/0x65]-aminocaproic acid was known in the art as a useful buffer of aqueous ophthalmic solutions. See, for example, Ushio.
Ushio teaches stable aqueous preparations for ophthalmic topical administration that contain a buffering component selected from a group consisting of several buffers, including phosphoric acid (phosphate) and [Symbol font/0x65]-aminocaproic acid (Abstract). Ushio further teaches that these preparations can be adjusted to pH as low as 5 (Abstract). As such, Ushio teaches that phosphate buffer and [Symbol font/0x65]-aminocaproic acid buffer are viable alternatives for maintaining an aqueous ophthalmic solution at a pH below 6. It therefore would have been obvious to one of skill in the art to replace or supplement the phosphate buffer of Akorn with the alternative buffer, [Symbol font/0x65]-aminocaproic acid, as taught by Ushio.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 extension fee 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 ALEXANDER K SHOWALTER whose telephone number is (571)270-0610. The examiner can normally be reached M-F 9:00 am to 5:00 pm, eastern time.
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/ALEXANDER K. SHOWALTER/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629