DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 05/21/2026 has been entered.
Withdrawn Rejections:
Applicant's amendments and arguments filed on 05/21/2026 are acknowledged and have been fully considered. The Examiner has re-weighed all the evidence of record. Any rejection and/or objection not specifically addressed below is herein withdrawn.
The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set of rejections and/or objections presently being applied to the instant application.
Claims 1-30 are pending and under examination.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 05/21/2026 is being considered by the examiner.
Claim Rejections - 35 USC § 112
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 the applicant regards as his invention.
Claims 1-24 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, or for pre-AIA the applicant regards as the invention.
Claim 19 recites “said ophthalmic solution has a temperature of 2-8ºC”, however, temperature is not ingredient or property of a composition, it is unclear how the solution has a temperature of 2-8ºC. Thus, the scope and boundary of claims are unclear, this is indefinite. For compact prosecution purpose, “said ophthalmic solution has a temperature of 2-8ºC” is examined as said ophthalmic solution is stored at a temperature of 2-8ºC. Claims 20-24 are rejected for depending on rejected claims 1, 13, 19 and 25.
Claims 1, 7, 13 and 19 recite “the aqueous ophthalmic solution does not contain any additional ingredients that is a chelating agent”, and there is no definition of chelating agent in applicant’s specification and only one example of chelating agent EDTA is provided ([0005]). Furthermore, applicants recite the claimed composition free of a chelating agent comprising polyol ([0009]) such as propylene glycol and glycerol (claim 1), This clearly indicates applicants do not regard propylene glycol and glycerol as chelating agent. However, Hong et al. teaches propylene glycol and glycerol as chelating agent (US20090131303, [0061]). This demonstrates that applicant’s chelating agent is different from those chelating agents known in the art, and since applicant failed to define “his own chelating agent” in the specification, the concept of chelating agent is unclear. When applicant recites negative limitation in the claims to exclude chelating agent without clear definition, one artisan in the art does not know what is excluded and what is included in the claim, thus, the scope and boundary of claims 1, 7, 13 and 19 are unclear. This is indefinite. For compact prosecution purpose, this limitation “the aqueous ophthalmic solution does not contain any additional ingredients that is a chelating agent” is examined as free of EDTA. Claims 2-6, 8-12, 14-18 and 20-24 are rejected for depending on rejected claims 1, 7, 13 or 19.
Response to Argument:
Applicants argued that “said ophthalmic solution has a temperature of 2-8ºC” is amended as “stored at a temperature”..
In response to this argument: this is not persuasive. Claim 19 is not amended.
Applicants argue that chelating agent is definite according to MPEP 2173.02 after applicants gave ordinary meaning for chelating agent.
In response to this argument: this is not persuasive. As discussed in the above 112 rejection, the ordinary meaning of chelating agent is inconsistent with their specification. When the specification states the meaning that a term in the claim is intended to have, the claim is examined using that meaning, in order to achieve a complete exploration of the applicant’s invention and its relation to the prior art. In re Zletz, 893 F.2d 319, 13 USPQ2d 1320 (Fed. Cir. 1989). MPEP 2173.05(a)I. Thus, the scope and boundary of chelating in claims are unclear, this is indefinite.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) 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 1-24 are rejected under 35 U.S.C. 103(a) as being unpatentable over Likitlersuang et al. (US20110178147) in view of Xia et al. (US20090220618), Mazess et al. (US20040053894) and Mosher et al. (US20120136072) and Chen et al. (WO2004000219).
Determination of the scope and content of the prior art
(MPEP 2141.01)
Likitlersuang et al. teaches a compositions and methods for controlling pupil dilation in a subject in need thereof. The compositions comprise about 0.001% to 2.0% by w/v or 0.01 % to about 1.0% by w/v of an alpha-adrenergic receptor antagonist selected from phentolamine, phentolamine mesylate, or another phentolamine salt; and at least one excipient selected from the group consisting of a buffer, tonicity agent, preservative, antioxidant, surfactant, solubilizer, cosolvent, and a combination thereof, and a pH of about 5.5 (abstract; page 1, [0005]). Likitlersuang et al. teaches a composition for controlling pupil dilation comprising about 0.02% to about 4% of a buffer, about 0.01 % to about 0.75% of a tonicity agent, about 0.005% to about 2.5% of a surfactant, about 0.001 % to about 3% of a solubilizer, and about 1 % to about 25% of a cosolvent by weight, and a pH of about 5.5 or about 4 to about 6.5. Tonicity agent includes alkai metal halide and non-ionic tonicity agent such as glycerol and mannitol (page 3, [0022-0025]). In certain embodiment, the composition comprises a cosolvent such as glycerin or mannitol in an amount of about 1% to about 25% (page 2, [0021]). This addresses all the limitation of mannitol as polyol and the amount in the composition. Carriers used in the disclosed composition are suitable for topical application, for example, water and water–miscible solvent including cellulose agent (page 2, [0020]). The composition optionally includes preservatives (page 3, [0026]). To increase the stability of the formulation and decrease alpha-l antagonist degradation or to slow the degradation rate, the composition can further comprise antioxidants, such as, ascorbic acid, vitamin E, N-acetylcarnosine (NAC), sorbic acid, ethylene diaminetetraacetic acid (EDTA), and a combination thereof (page 3, [0027]). The amount of buffer substance added is that necessary to ensure and maintain a physiologically tolerable pH range. In one embodiment, the buffer agent is acetate (page 3, [0024]). The most common acetate is sodium acetate (Mw 82), if the density of liquid composition is about 1g/ml, the conversion of about 0.02% to about 4% of a buffer into mM is about (0.02% x1000/82) x1000 to about (4% x1000/82)x1000 = about 2.4mM to 488mM, and this range encompasses all the instant claimed range of sodium acetate (buffer), and acetic acid is inherently existing in the buffer as ionic pair of buffer sodium acetate/ acetic acid. This addresses all the limitation of sodium acetate as buffer and its concentration.
Xia et al. teaches in certain embodiments, however, an ophthalmic solution of the present invention can be desirably free of chelating agents. In some other embodiments, it may also be advantageous to exclude a chelating agent (page 3, [0037]).
Mazess et al. teaches certain chelating agents such as EDTA have been implicated in adverse effects such nephrotoxicity and renal tubular necrosis (page 2, [0013]).
Mosher et al. teaches a composition comprising phentolamine (page 9, [0100]) and stabilizer such as glycerol, mannitol, sorbitol, etc. to stabilize the therapeutic agent against physical, chemical, or biochemical process that would reduce the therapeutic activity of the agent (page 11, [0129]; page 14, [0152]) in the form of ophthalmic (page 10, [0109]).
Chen et al. teaches the 48-week data show phentolamine mesylate formulations 1-4 to be relatively stable at storage temperatures of 25°C and lower. The data show that formulation 1 stored at 2-8°C should remain in specification (i.e., less than 10%) loss in concentration and purity) for more than 180 weeks, but has a predicted shelf life, based on the lower 95% confidence limit, of 108 weeks. The data show that formulation 1 stored at 25°C should remain in specification for 108 weeks, but has a predicted shelf life, based on the lower 95% confidence limit, of 69 weeks. The data show that formulation 2 stored at 25°C should remain in specification for 103 weeks, but has a predicted shelf life, based on the lower 95% confidence limit, of 63 weeks. The data show that formulation 3 stored at 25°C should remain in specification for 88 weeks, but has a predicted shelf life, based on the lower 95% confidence limit, of 61 weeks. The data show that formulation 4 stored at 25°C should remain in specification for 115 weeks, but has a predicted shelf life, based on the lower 95% confidence limit, of 60 weeks (page 50, line 5 to page 51, line 5).
Ascertainment of the difference between the prior art and the claims
(MPEP 2141.02)
The difference between the instant application and Likitlersuang et al. is that Likitlersuang et al. do not expressly teach to exclude EDTA. This deficiency in Likitlersuang et al. is cured by the teachings of Xia et al., Mazess et al. and Mosher et al.
Finding of prima facie obviousness
Rational and Motivation (MPEP 2142-2143)
It would have been obvious to one of ordinary skill in the art at the time the claimed invention was made to prepare a composition free of EDTA, as suggested by Xia et al., Mazess et al. and Mosher et al. and produce the instant invention.
One of ordinary skill in the art would have been motivated to prepare a composition comprising 0.25% to 2.0% by w/v phentolamine mesylate, a buffer (1mM to 6mM of sodium acetate) and about 1% to 6% of a polyol (glycerol or mannitol) in the water solution at pH 4.5 to 5.5 since Likitlersuang et al. teaches a composition comprising about 0.001% to 2.0% by w/v phentolamine mesylate; and at least one excipient selected from the group consisting of a buffer, tonicity agent, preservative, antioxidant, surfactant, solubilizer, cosolvent, and a combination thereof; it is obvious for one of ordinary skill in the art to prepare a composition comprising 0.001% to 2.0% by w/v phentolamine mesylate, a buffer (sodium acetate) and a cosolvent (mannitol, also function as non-ionic tonicity agent) in the water solution. Likitlersuang et al. teaches about mannitol at an amount of 1-25%, sodium acetate (acetic acid is inherently existing) at an amount of about 2.4mM to 488mM. It is obvious for one of ordinary skill in the art to prepare the instant claimed invention with reasonable expectation of success in the absence of evidence to the contrary.
One of ordinary skill in the art would have been motivated to exclude EDTA from the composition because EDTA, which is recited as additional components to stabilize the composition by Likitlersuang et al., is not required since glycerol or mannitol functions as stabilizer for the composition comprising phentolamine as suggested by Mosher et al. Furthermore, it is desirable and advantage to exclude EDTA to avoid adverse effect as suggested by Xia et al. and Mazess et al. MPEP 2144.04 IIA states, omission of an element and its function is obvious if the function of the element is not desired or required. In the current situation, the stabilizing function from EDTA is not required since glycerol or mannitol functions as stabilizer, and side effect of EDTA is not desired. Therefore, it is obvious for one of ordinary skill in the art to exclude EDTA to have a composition free of EDTA and produce the instant claimed invention with reasonable expectation of success. Furthermore, since Likitlersuang et al. teaches vitamin E, N-acetylcarnosine (NAC) and sorbic acid (none of these three antioxidant appears to be chelating agent) as alternative to EDTA to stabilize the composition, it is obvious for one artisan in the art to choose vitamin E, N-acetylcarnosine (NAC) or sorbic acid to replace EDTA (and exclude chelating agent) to stabilize and produce instant claimed invention with reasonable expectation of success.
Regarding consisting essentially of, for the purposes of searching for and applying prior art under 35 U.S.C. 102 and 103, absent a clear indication in the specification or claims of what the basic and novel characteristics actually are, "consisting essentially of" will be construed as equivalent to "comprising.". MPEP 2111.03 III.
Regarding “said ophthalmic solution has a temperature of 2-8ºC” is examined as said ophthalmic solution is stored at a temperature of 2-8ºC. Since the storage of the composition is not property of the claimed composition, it is not limiting. In arguendo that the storage at temperature of 2-8ºC is limiting, one of ordinary skill in the art would been motivated to store the composition comprising phentolamine mesylate at 2-8ºC because the composition comprising phentolamine mesylate stored at 2-8ºC has significantly longer shelf life than the composition comprising phentolamine mesylate stored at 25ºC as suggested by Chen et al. Since it is preferred to have longer shelf life, it is obvious for one of ordinary skill in the art to store the composition comprising phentolamine mesylate at 2-8ºC and produce instant claimed invention with reasonable expectation of success.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103(a).
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Argument:
Applicants argued that EDTA would not be removed from formulation, and all arguments in section I and II are incorporated herein by reference.
In response to this argument: this is not persuasive. As discussed in the above 103 rejections, even EDTA is recited in working example, one of ordinary skill in the art would have been motivated to exclude EDTA from the composition because EDTA, which is recited as additional components to stabilize the composition by Likitlersuang et al., is not required since glycerol or mannitol functions as stabilizer for the composition comprising phentolamine as suggested by Mosher et al. Furthermore, it is desirable and advantage to exclude EDTA to avoid adverse effect as suggested by Xia et al. and Mazess et al. MPEP 2144.04 IIA states, omission of an element and its function is obvious if the function of the element is not desired or required. In the current situation, the stabilizing function from EDTA is not required since glycerol or mannitol functions as stabilizer, and side effect of EDTA is not desired. Therefore, it is obvious for one of ordinary skill in the art to exclude EDTA to have a composition free of EDTA and produce the instant claimed invention with reasonable expectation of success. It is well settled, however, that the teachings of a reference are not limited to the working examples. See in re Miiis and Pairner, 470 F.2d 649 (CCPA 1972) ("[A] reference is not limited to the disclosure of specific working examples."), In re Chapman and Cosby, 357 F.2d 418, (CCPA 1966) ("A reference can be used for all it realistically teaches, and is not limited to the disclosures in its specific illustrative examples."), and In re Widmer, Batzer and Nikles, 353 F2d 752 (CCPA 1965) ("Examples in a reference are merely that, exemplary of the broader disclosure, all of which is available for what it clearly teaches."). Regarding the Table VII of Chen ( it is noted that Chen et al. (WO2004000219) does not teach Table VII, and the examiner can only relied on the data provided by applicants in arguments to reply), this does not teach EDTA is necessary at least for the following reasons. Firstly, the stability test is performed at pH 3.5 and 25ºC, the claimed composition is at pH about 4.0 to about 7.5 at 2-8 ºC; and prior art composition from Likitlersuang has pH of about 5.5 or about 4 to about 6.5, there is no evidence to show that there is significant difference on stability at pH about 4.0 to about 7.5 at 2-8 ºC, especially applicants submits that pH is critical in the following arguments (section III). Secondly, Likitlersuang recites EDTA as alternative to ascorbic acid, vitamin E, N-acetylcarnosine (NAC) or sorbic acid as antioxidant stabilizer, and EDTA could be replaced by ascorbic acid, vitamin E, N-acetylcarnosine (NAC) or sorbic acid. Furthermore, it has been held that a prior art reference must either be in the field of the inventor’s endeavor or, if not, then be reasonably pertinent to the particular problem with which the inventor was concerned, in order to be relied upon as a basis for rejection of the claimed invention. See In re Oetiker, 977 F.2d 1443, 24 USPQ2d 1443 (Fed. Cir. 1992). In this case, Xia et al. and Mazess et al. are properly relied on for teaching adverse effect of EDTA. Regarding the arguments that some product in the market contains EDTA, it is argued that one artisan in the art knows how to balance the pro and con of EDTA in the formulation, and it is always desirable to exclude EDTA when possible. Therefore, the 103 rejection is still proper.
Applicants argued that about excellent stability of the claimed invention as well as criticality of claimed pH range. All arguments in section III are incorporated herein by reference.
In response to this argument: this is not persuasive. Applicants failed to prove that prior art composition is not stable, especially prior arts teach the same composition, and this same composition is expected to have the same properties such as stability over weeks and months. Regarding the criticality of claimed pH range, applicants failed to provide sufficient number of tests in and out of claimed range. Thus, the 103 rejection is still proper.
Applicants argue that it is not obvious to store the formulation at 2-8ºC. All arguments in this section are incorporated herein by reference.
In response to this argument: this is not persuasive. Chen et al. is relied on for teaching formulation comprising phentolamine unstable and being stored at 2-8ºC, there is no evidence to show that composition without EDTA would behave differently regarding stability, it is still obvious for one artisan in the art to store formulation comprising phentolamine at 2-8ºC for better stability. Furthermore, the storage temperature of claimed invention is not limiting because there is no difference between a composition stored at 2-8ºC and a composition comprising the same ingredients stored at 25 ºC. Thus, the 103 rejection is still proper.
MPEP 2141 III states: “The proper analysis is whether the claimed invention would have been obvious to one of ordinary skill in the art after consideration of all the facts.” Respectfully, after weighing all the evidence, the Examiner has reached a determination that the instant claims are not patentable in view of the preponderance of evidence and consideration of all the facts which is more convincing than the evidence which has been offered in opposition to it.
Conclusion
Claims 1-24 are rejected and claims 25-30 are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JIANFENG SONG. Ph.D. whose telephone number is (571)270-1978. The examiner can normally be reached M-F 8-5.
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/JIANFENG SONG/Primary Examiner, Art Unit 1613
Prosecution Insights