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 .
Election/Restrictions
Applicant’s election without traverse of Group I, drawn to claims 1-18 in the reply filed on 09/08/2025 is acknowledged. Claims 19-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected entities, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 09/08/2025.
Status of the Claims
The status of the claims are as follows:
Claims 1-20 are pending.
Claims 19-20 are withdrawn.
Claims 1-15 and 17-18 are rejected.
Claims 16 and 18 are objected to.
Priority
Acknowledgement is made that Instant Application 18/901,715, filed on 09/30/2024, is a Continuation in Part of Application 18/529,137, filed on 12/05/2023, now U.S. Patent 12,102,683 B2, which is a Continuation of PCT/CN2023/074701, filed on 02/07/2023, which claims Foreign Priority from CN202210869988X, filed on 07/22/2022. Acknowledgment is made of applicant's claim for foreign priority based on an application filed in China on 07/22/2022. It is noted, however, that applicant has not filed a certified copy of the application as required by 37 CFR 1.55. Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 09/30/2024 and 03/23/2026 is/are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Interpretation
Claim 18 recites the limitation “which is substantially from water.” In view of the specification which recites, “No water is contained in the formulation, which improves the stability of diltiazem hydrochloride” (page 8, line 8), the claim will be interpretated as “which is substantially free from water.”
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.
Claim 18 is 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Specifically, the claim is directed to a composition that is “substantially [free] from water.”
The above phrase renders the scope of the claim ambiguous because it allows for multiple interpretations. For example, food products may consider 5% water content as “substantially free of water”, while a lyophilizate would require much less. Accordingly, the claim does not inform one of ordinary skill in the art to what degree water may be present with reasonable certainty.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
Claim(s) 1, 4-5, 8-15 and 17-18 is/are rejected under 35 U.S.C. 103 as being unpatentable over de Souza Teixeira (US 2022/0151918 A1. Published 05/19/2022) in view of Geoghegan (US 4,891,230. Date of Patent: 01/02/1990).
Claim 1 is directed to a pharmaceutical composition of diltiazem hydrochloride in the form of a gel comprising diltiazem hydrochloride and excipients, wherein the excipients comprise:
Propylene glycol;
One or both of benzoic acid and tartaric acid;
A gel matrix, wherein the gel matrix comprises one or both of povidone and hydroxypropyl cellulose; and
Optionally tocopherol.
de Souza Teixeira teaches topical pharmaceutical compositions for treatments of anal fissures and hemorrhoids, including the postoperative period of hemorrhoidectomy (title, abstract). The topical pharmaceutical compositions comprise an anal dilator, a mucoadhesive polymer, and a non-aqueous vehicle (abstract). A particular composition (hereafter referred to as “composition I”) includes diltiazem hydrochloride, propylene glycol, hydroxypropyl cellulose, and alpha-tocopherol (page 4, paragraph 0061):
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de Souza Teixeira further teaches the preferred form of the topical pharmaceutical composition is a gel because gels overcome some drawbacks of ointment formulations (page 2, paragraph 0018). Gels are described as semi-rigid systems composed of a three-dimensional network with interlacing particles or macromolecules solvated by the dispersed phase, wherein a gel can be a hydrogel (aqueous continuous phase) or an organogel (organic continuous phase) (page 2, paragraph 0018). Organogels have improved properties over hydrogels and are therefore the preferred form of the topical pharmaceutical composition because hydrogels (i) create an environment conducive to the proliferation of microorganisms, which rely on water to survive; (ii) cause direct chemical change to the active agents by reactions such as hydrolysis caused by the medium; and (iii) physical instability of the formulation. comprising an environment that is less (page 2, paragraph 0019). Hydroxypropyl cellulose is taught to be insoluble in glycerol and other aliphatic hydrocarbons and thereby provides the organogel form of the topical pharmaceutical composition (page 3, paragraphs 0041-0042). de Souza Teixeira further teaches composition I may include malic acid as an antioxidant, suggesting this formulation is tolerant of alpha-hydroxy acids (page 4, paragraph 0046).
The difference between the above teaching and the Instant Application is that de Souza Teixeira fails to teach a composition that further comprises tartaric acid.
However, Geoghegan teaches formulations of diltiazem to for controlled oral absorption and good stability over normal shelf-life periods of eighteen months to two years, and which contains only synthetic polymeric materials (column 2, lines 16-25). The formulations comprise diltiazem or a pharmaceutically acceptable salt thereof in association with an organic acid, the diltiazem component and the organic acid being present in a ratio of from 50:1 to 1:1, and a multi-layer membrane surrounding said core and containing a major proportion of a pharmaceutically acceptable film-forming, water insoluble, synthetic polymer (column 2, lines 30-40). Example 6 is provided (column 10, lines 10-40), wherein a composition comprising diltiazem hydrochloride, succinic acid, hydroxylpropylmethyl cellulose, and propylene glycol is described. Geoghegan further teaches the succinic acid may be substituted for tartaric acid, a type of alpha-hydroxy acid (column 2, lines 60-65) and the hydroxylpropylmethyl cellulose can be substituted for hydroxypropyl cellulose.
One of ordinary skill in the art would have been motivated to combine the teachings above because they teach the same field of endeavor of diltiazem hydrochloride compositions. de Souza Teixeira notes the susceptibility of diltiazem to hydrolyze in hydrogels and offers organogels as a more stabilizing alternative. However, the two largest components of the composition of de Souza Teixeira is propylene glycol (32%) and diethylene glycol monoethyl ether (22.96%), both of which are completely miscible in water. Therefore, one would expect similar degradation of diltiazem degradation over long-term storage due to the absorption of moisture from the air. Geoghegan teaches diltiazem hydrochloride compositions further comprising an organic acid, including tartaric acid, improve the stability of diltiazem hydrochloride over long-term storage. Furthermore, the compositions of de Souza Teixeira are taught to be tolerant of alpha-hydroxy acids, while the compositions of Geoghegan are taught to be tolerant of hydroxypropyl cellulose and propylene glycol. As such, said skilled artisan would have found it prima facie obvious to add tartaric acid to the composition of de Souza Teixeira to arrive at the claimed invention.
Claim 4 is directed to the diltiazem hydrochloride pharmaceutical composition of claim 1, wherein, based on percentage by weight in the composition, the diltiazem hydrochloride accounts for 1%-5%, the tartaric acid accounts for 0.05%-0.30%, and the gel matrix accounts for 5%-10%.
de Souza Teixeira teaches composition I, which is comprised of diltiazem hydrochloride (2%) and hydroxypropyl cellulose gel matrix (4%) (page 4, paragraph 0061). Geoghegan teaches the diltiazem component and the organic acid (e.g., tartaric acid) should be present in a ratio of from 50:1 to 1:1 (column 2, lines 30-35), which encompasses the claimed range.
The difference between the combined teachings above and the Instant Application is that the described composition fails to teach the hydroxypropyl cellulose gel matrix being present at 5%-10%.
However, de Souza Teixeira teaches the hydroxypropyl cellulose component can be present at an amount between 0.5-10% (page 4, paragraph 0044). Therefore, one of ordinary skill in the art could have arrived at the instant invention through routine optimization.
Claim 5 is directed to the diltiazem hydrochloride pharmaceutical composition of claim 1, wherein, based on percentage by weight in the composition, the diltiazem hydrochloride accounts for 1%-4%, the tartaric acid accounts for 0.1%-0.2%, and the gel matrix accounts for 7%-9%.
For the reasons described above, the composition of de Souza Teixeira in view of Geoghegan comprise the claimed components in the claimed proportions.
Claim 8 is directed to the diltiazem hydrochloride pharmaceutical composition of claim 1, wherein the gel matrix comprises hydroxypropyl cellulose.
de Souza Teixeira teaches composition I, which is comprised of a hydroxylpropyl cellulose organogel (page 4, paragraph 0061).
Claim 9 is directed to the diltiazem hydrochloride pharmaceutical composition of claim 1, wherein the gel matrix comprises povidone.
de Souza Teixeira teaches composition I, which is comprised of a hydroxypropylcellulose organogel (page 4, paragraph 0061).
The difference between the composition of de Souza Teixeira and the Instant Application is that composition fails to teach wherein the gel matrix comprises povidone.
However, de Souza Teixeira teaches polyvinylpyrrolidone (povidone) as a suitable substitute for hydroxypropylmethyl cellulose (page 3, paragraph 0038).
Accordingly, one of ordinary skill in the art could have applied prong (B) of the KSR rationale to substitute hydroxylpropmethyl cellulose for povidone and arrive at the current invention.
Claim 10 is directed to the diltiazem hydrochloride pharmaceutical composition of claim 1, wherein the gel matrix comprises povidone and hydroxypropyl cellulose.
de Souza Teixeira teaches composition I, which is comprised of a hydroxypropylcellulose organogel (page 4, paragraph 0061).
The difference between the composition of de Souza Teixeira and the Instant Application is that composition fails to teach wherein the gel matrix comprises povidone.
However, de Souza Teixeira teaches polyvinylpyrrolidone (povidone) as a suitable substitute for hydroxypropylmethyl cellulose (page 3, paragraph 0038).
Accordingly, one of ordinary skill in the art could have applied prong (A) of the KSR rationale to combine two known elements with similar properties to yield predictable results.
Claim 11 is directed to the diltiazem hydrochloride pharmaceutical composition of claim 1, wherein the diltiazem hydrochloride accounts for 2% or 4% by weight.
de Souza Teixeira teaches composition I, which is comprised of 2% diltiazem hydrochloride (page 4, paragraph 0061).
Claim 12 is directed to the diltiazem hydrochloride pharmaceutical composition of claim 1, wherein, based on percentage by weight in the composition, the propylene glycol is greater than 80%.
de Souza Teixeira teaches composition I, which is comprised of 32% propylene glycol (page 4, paragraph 0061).
The difference between the above teaching and the Instant Application is that composition I fails to teach where propylene glycol is present in greater than 80%.
However, composition I further includes polyethylene glycol 400 (PEG 400) at 16%, and diethylene glycol monoethyl ether at 22.96%, and caprylocaproyl macrogol-8 glycerides at 16%. Propylene glycol, PEG 400, diethylene glycol monoethyl ether and caprylocaproyl macrogol-8 glycerides are all taught to be interchangeable non-aqueous vehicles (page 2, paragraph 0027). Therefore, one of ordinary skill in the art would have had a reasonable expectation of success to apply prong (B) of the KSR rationale to substitute all three of PEG 400, diethylene glycol monoethyl ether and caprylocaproyl macrogol-8 glycerides with propylene glycol, thus arriving at the claimed invention.
Claim 13 is directed to the diltiazem hydrochloride pharmaceutical composition of claim 12, wherein, the pharmaceutical composition further comprises tocopherol.
de Souza Teixeira teaches composition I, which is comprised of tocopherol (page 4, paragraph 0061).
Claim 14 is directed to the pharmaceutical composition of claim 13, wherein, based on percentage by weight in the composition, the tocopherol accounts for up to 1% in the composition.
The tocopherol of composition I is present in 0.05%.
Claim 15 is directed to the diltiazem hydrochloride pharmaceutical composition of claim 13, wherein, based on percentage by weight in the composition, the tocopherol accounts for 0.1%-0.75% in the composition.
de Souza Teixeira teaches composition I, which is comprised of 0.05% tocopherol (page 4, paragraph 0061).
The difference between composition I and the Instant Application is that de Souza Teixeira fails to teach where tocopherol is 0.1%-0.75%.
However, de Souza Teixeira teaches tocopherol can be present from 0.01%-1.0% by weight (page 4, paragraph 0046). Therefore, one of ordinary skill in the art would have had a reasonable expectation of success to routinely optimize the amount of tocopherol to arrive at an amount that falls within the claimed range.
Claim 17 is directed to the diltiazem hydrochloride pharmaceutical composition of claim 1, wherein deacetyl diltiazem is no more than 3%.
de Souza Teixeira teaches composition I, which does not comprise any deacetyl diltiazem (page 4, paragraph 0061).
Claim 18 is directed to the diltiazem hydrochloride pharmaceutical composition of claim 1, wherein the pharmaceutical composition is substantially free from water.
de Souza Teixeira teaches composition I, which is free from water (page 4, paragraph 0061).
Claim(s) 2-3 is/are rejected under 35 U.S.C. 103 as being unpatentable over de Souza Teixeira in view of Velga Abreu Rocha (EP 1 516 622 B1. Published 10/24/2007).
The teachings of de Souza Teixeira are discussed above and incorporated herein by reference.
Claim 2 is directed to the diltiazem hydrochloride pharmaceutical composition of claim 1, wherein, based on percentage by weight in the composition, the diltiazem hydrochloride accounts for 1%-5%, the benzoic acid accounts for 0.1%-5.0%, and the gel matrix accounts for 5%-10%.
The difference between de Souza Teixeira and the Instant Application is that de Souza Teixeira fails to teach the use of benzoic acid at 0.1%-5.0%.
However, Velga Abreu Rocha teaches stable diltiazem pharmaceutical compositions for cutaneous application, comprising only oily components (abstract). The diltiazem hydrochloride is combined to oily excipients, to one or more tensioactive agents, and one or more preservatives, in the absence of water or any other aqueous excipient (page 2, paragraph 0012). The preservative is used to prevent conversion of diltiazem into deacetyl diltiazem. Example 8 is provided, in which an oily composition comprising diltiazem hydrochloride (6%) and benzoic acid (0.2%) is described (page 8, paragraphs 0063-0065).
One of ordinary skill in the art would have been motivated to combine the above teachings because they both teach the same field of endeavor of diltiazem hydrochloride pharmaceutical compositions. As discussed above, de Souza Teixeira notes the susceptibility of diltiazem to hydrolyze in hydrogels and offers organogels as a more stabilizing alternative. Said skilled artisan would have found it prima facie obvious to combine the benzoic acid preservative to the water-free composition I with a reasonable expectation of success of impeding hydrolysis of the active agent.
Claim 3 is directed to the diltiazem hydrochloride pharmaceutical composition of claim 1, wherein, based on percentage by weight in the composition, the diltiazem hydrochloride accounts for 1%-4%, the benzoic acid accounts for 0.25%-0.75%, and the gel matrix accounts for 7%-9%.
The difference between the diltiazem hydrochloride pharmaceutical composition formed from the combined teaching of de Souza Teixeira in view of Velga Abreu Rocha is that the combined composition fails to teach where the benzoic acid is present in an amount between 0.25%-0.75%.
However, the composition of Velga Abreu Rocha comprises 0.2% benzoic acid (page 8, paragraph 0064). One of ordinary skill in the art could would have known to assess the degree to which diltiazem had converted into deacetyl diltiazem and increase the amount of benzoic acid as necessary to prevent deterioration of the active ingredient. Therefore, said skilled artisan could have arrive at an amount that falls within the claimed range through routine optimization.
Claim(s) 6-7 is/are rejected under 35 U.S.C. 103 as being unpatentable over de Souza Teixeira in view of Geoghegan and in further view of Velga Abreu Rocha.
The teachings of de Souza Teixeira in view of Geoghegan and the teachings of de Souza Teixeira in view of Velga Abreu Rocha are discussed above and incorporated herein by reference.
Claim 6 is directed to the diltiazem hydrochloride pharmaceutical composition of claim 1, wherein both benzoic acid and tartaric acid are used.
The difference between the teaching of de Souza Teixeira in view of Geoghegan is that the combined teachings fail to teach the use of benzoic acid in the diltiazem hydrochloride pharmaceutical composition.
However, as discussed above, Velga Abreu Rocha teaches the use of benzoic acid in diltiazem hydrochloride pharmaceutical compositions.
One of ordinary skill in the art would have been motivated to combine the teaching of Velga Abreu Rocha with the combined teachings of de Souza Teixeira in view of Geoghegan because they all teach the same field of endeavor of diltiazem hydrochloride pharmaceutical compositions. Furthermore, de Souza Teixeira teaches the susceptibility of diltiazem to hydrolyze, while both the tartaric acid of Geoghegan and benzoic acid of Velga Abreu Rocha are taught to preserve diltiazem hydrochloride. Therefore, said skilled artisan could have applied prong (A) of the KSR rationale to combine different agents that are known to have the same properties to achieve the predictable result of preserving diltiazem hydrochloride.
Claim 7 is directed to the diltiazem hydrochloride pharmaceutical composition of claim 6, wherein the pharmaceutical composition further comprises tocopherol.
The diltiazem pharmaceutical composition from the combined teachings of de Souza Teixeira in view of Geoghegan and in further view of Velga Abreu Rocha comprises tocopherol.
Claim Objections
Claim 18 is objected to for containing a minor informality. The claim recites the limitation “which is substantially from water.” Appropriate action is required.
Claim 16 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. The claim is directed to the diltiazem hydrochloride pharmaceutical composition comprising >80% propylene glycol, 1%-5% diltiazem hydrochloride, 0.1%-5.0% benzoic acid when present, 0.25%-0.5% tocopherol when present, and 5%-10% of the gel matrix accounts
The closest prior art to the claim is de Souza Teixeira, in which composition I is taught. Composition I comprises 32% propylene glycol, 16% polyethylene glycol 400 (PEG 400), 22.96% diethylene glycol monoethyl ether, 16% caprylocaproyl macrogol-8 glycerides, 2% diltiazem, 0.05% tocopherol, and 4% gel matrix, while benzoic acid is not present.
To arrive at the claimed invention, one of ordinary skill in the art must first substitute all of PEG 400, diethylene glycol monoethyl ether, and caprylocaproyl macrogol-8 glycerides to propylene glycol to arrive at an amount of propylene glycol >80%. Said artisan must then optimize the proportion tocopherol and increase the amount by 5-times, and then further optimize the amount of hydroxypropyl cellulose.
While it would be obvious to optimize at most two of propylene glycol, tocopherol, or the gel matrix to arrive, one of ordinary skill in the art would not find it obvious to routinely optimize all three components at arrive at the claimed invention.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Paul Arcoria whose telephone number is (571)272-8719. The examiner can normally be reached Mon-Fri 8:00-5:00 EST.
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/P.A./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
