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 .
DETAILED ACTION
Response to Amendment
Acknowledged is made of amendment filed 03/06/2026, wherein claim 50 is amended.
Election/Restrictions
Applicant elected without traverse of Group I invention, pharmaceutical composition in the reply filed on 03/18/2024.
Status of Claims
Claims 1, 22, 24-29, 35-36, 38, 43, and 45-50 are pending.
Claims 35-36 remain withdrawn.
Claims 1, 22, 24-29, 38, 43, and 45-50 are currently under examination.
Response to Declaration
The Declaration under 37 CFR 1.132 by Roland Bodmeier filed 03/06/2026 is fully considered, but NOT persuasive to overcome rejection of claims over Basnakian, in view of Shu, CYSTARAN® label , Longo and Pescina under 35 U.S.C. 103.
Bodmeier Declaration focused on the limitation “wherein the composition has a pH from 5.0 to 6.5; and wherein the composition is an aqueous solution” and argues against the reference on the record individually, and “the combination of references when considered as a whole teaches away from these
Limitations”(para 8-11).
RESPONSE: Please note the obviousness of limitation “wherein the composition has a pH from 5.0 to 6.5; and wherein the composition is an aqueous solution” is based on the combined teachings of prior art on the record. As elaborated in 103 rejection and response in previous office action, Basnakian teaches aminothiol drug (e.g. cysteamine HCl salt ) and zinc salt (zinc chloride or zinc acetate, etc.) form complex in aqueous solution(pH 10 or neutral), and aqueous solution embodiments may be adjusted with acids or bases such as hydrochloric acid or sodium hydroxide, and buffer (e.g. acetate, citrate, or phosphate). Shu also teaches the thiol group of cysteamine and zinc chloride forms coordination form within the cysteamine/Zn chelate/complex which protect/reduce the oxidation of cysteamine and would provide improved stability of cysteamine and mask the unpleasant order of sulfur. A skilled artisan would have known CYSTARAN is cysteamine ophthalmic aqueous solution approved since 1994. Pescina teaches cysteamine hydrochloride (0.44% free base) in variety combination with different excipient and stability study at different pH range( e.g. pH 4.2 to 7.4) . Pescina explicitly teaches cysteamine aqueous solution with pH range from 5.01 ± 0.10 to 6.37 ± 0.11 (See Table 3) that read on instant claimed pH range. In search for stabilized cysteamine eye drop solution, a skilled artisan would have known to adjust the pH of cysteamine aqueous solution accordingly. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. MPEP 2144.05.
Bodmeier Declaration argues Basnakian and Shu's synthetic protocols conclude with
filtering off and purifying the precipitated a zinc complex and modifying Basnakian
and Shu would contradict their intended purposes, which are to synthesize, isolate, and purify filtered off zinc complexes (para 10).
RESPONSE: The synthesis /precipitation of zinc complex/chelate is NOT Basnakian’s final purpose as Bodmeier Declaration argues. The final purpose of Basnakia is to formulate cysteamine zinc complex into composition and method of using the composition comprising aminothiol drug (cysteamine) zinc complex/chelate for cytoprotection. Instantly claimed invention relates to pharmaceutical compositions comprising cysteamine-zinc complexes having therapeutic properties. Thus, cysteamine-zinc complexes taught by Basnakian and modification thereof is not considered as “teaching away”.
In response to Bodmeier Declaration argument about “teach away” , MPEP 2123(I) and (II) provides the following guidance. MPEP 2123(I): “A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). See also UpsherSmith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005) (reference disclosing optional inclusion of a particular component teaches compositions that both do and do not contain that component)”. MPEP 2123(II):“Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). "A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use." In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994) ….. "[t]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004)”.
Bodmeier Declaration argues about unexpected result: compositions prepared at the
claimed pH range showed enhanced stability,..., obtained additional experimental data of other representative zinc anion species (zinc acetate and zinc sulfate) also demonstrated enhanced stability of cysteamine compositions at the claimed pH range (See para 11).
RESPONSE: As stated in MPEP 716.02(d): “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980)”.
Instant claim 1 is drawn to pharmaceutical composition genus comprising cysteamine or a pharmaceutically acceptable salt thereof, variety of zinc salt and other ingredients without any amount/concentration of cysteamine and zinc salt and ratio thereof. Instantly disclosed working example (See Examples 1 and 2, Fig 1-4) are based on embodiments comprising cysteamine , zinc salt and other inactive ingredients (e.g. EDTA, benzalkonium chloride, etc.) at specific amount/ ratio. It’s noted F16 to F21 comprising cysteamine and zinc chloride at different ratio (2:1, 4:1 and 8:1) at pH from 5 to 6 have different stability profile. For example, the total impurity for F21 comprising CH:ZnCl2 (8:1) in mannitol/HPMC at pH 6.0 is 100% (See Figure 4). Thus, Applicant’s argument regarding the unexpected stability at pH 5 to 6.5 does not commensurate with instantly claimed scope of pharmaceutical composition genus comprising cysteamine or a pharmaceutically acceptable salt thereof, and variety of zinc salt, and other ingredients without any amount/concentration of cysteamine and zinc salt and ratio thereof.
Response to Arguments
Applicant's remarks filed 03/06/2026 have been fully considered. Any objection and rejection found in the previous Office Action and not repeated herein has been withdrawn in view of amendment and Applicant’s persuasive arguments .The text of those sections of Title 35 U.S. Code not included in this action can be found in a prior Office action.
Applicant's argument are similar to Bodmeier Declaration: (1) the combination of references does not teach, suggest, or even hint at the claimed limitations "wherein the composition has a pH from 5.0 to 6.5; and wherein the composition is an aqueous solution"; (2) modifying Basnakian and Shu as alleged by the Examiner render the references unfit for their intended purposes; and (3) the combination of references teaches away from the claimed limitations. Please see response to Bodmeier Declaration as elaborated above.
Priority
The instant application 17/281,585 filed on 03/31/2021 is a 371 of PCT/US2019/054873 filed on 10/04/2019 and claims benefit of US provisional application 62/742,336 filed on 10/06/2018.
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 for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or non-obviousness.
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 for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 22, 24-29, 38, 43, and 45-50 are rejected under 35 U.S.C. 103 as being unpatentable over Basnakian et al. US 2009/0042850 A1, Applicant's IDS dated 10/21/2021, under “US Patent Application Publications”, Cite# 2), in view of Shu et al.( Bioinorganic Chemistry and Applications, Volume 2016, Article ID 2691253, Applicant’s IDS dated 10/21/2021, “Synthesis, Crystal Structure, Spectroscopic Properties, and Interaction with Ct-DNA of Zn(II) with 2-Aminoethanethiol Hydrochloride Ligand’’), CYSTARAN®(Cysteamine Ophthalmic Solution, RxList dated September 25, 2017, Applicant’s IDS dated 10/21/2021), Longo et al.(US 8,389,014 B2) and Pescina et al. (European Journal of Pharmaceutics and Biopharmaceutics, October 2016, Volume 107, Pages 171-179, Applicant’s IDS dated 05/16/2024, http://dx.doi.org/10.1016/j.ejpb.2016.07.009, “ Effect of pH and penetration enhancers on cysteamine stability and trans-corneal transport”).
Regarding cysteamine and zinc salt, Basnakian discloses a pharmaceutical composition comprising zinc chelate of aminothiol compound (e.g. cysteine, cysteamine, etc.) and zinc ion for cytoprotection (See abstract, [0035], [0075], claims 1, 4). Basnakian teaches Zn-chelates (Zn-cysteamine) have dual cytoprotective effects wherein Zn2+ directly inhibits nucleases and the aminothiol component has antioxidant activity and indirectly inhibits nucleases by preventing nuclease induction and release ( [0033]). Basnakian teaches Zn-chelates provides better antioxidant activity and better radioprotection than the ligand (See Example 4, [0136], [0138]-[0140]).
Basnakian explicitly teaches the aminothiol ligand is cysteamine (See [0075], Table 2-6, claims 21-23) and teaches zinc-cysteamine chelate (Zn-Cyst) comprising 2:1 molar ratio of aqueous aminothiol and ZnCl2 (See [0131])(which reads on instant claims 22, 46-47).
Basnakian discloses the compositions include excipient such as oral dispersing agent, stabilizer, preservative, diluent, lubricant, taste masking agents, flavor-modifying agent, etc. and combinations thereof (See [0077]-[0090]) (which reads on limitation of pharmaceutical acceptable excipient).
Regarding the limitation of pH and aqueous solution, Basnakian teaches preparation of zinc chelate of cysteamine from hydrochloride salt of cysteamine with zinc chloride in aqueous solution at pH 10 (See [0131]). Basnakian also teaches preparation of zinc chelate of other thiol drug/ligand with zinc acetate without acid or base in aqueous solution which is considered as neutral pH about 6.5-7(See [0132]). Basnakian disclosed embodiments of dosage form for parenteral administration in aqueous solution (e.g. in water, saline solution, a pharmaceutically acceptable polyol such as glycerol, etc.) (which also reads on instant claim 28) (See [0103]). Basnakian teaches pH of the aqueous solution may be adjusted with acids or bases such as hydrochloric acid or sodium hydroxide, and buffer such as acetate, citrate, or phosphate (See [0103]). For intended dosage form in aqueous solution, a skilled artisan would know to adjust pH of the aqueous solution to keep cysteamine/ Zn chelate/complex in the aqueous solution without filtering off the cysteamine/ Zn chelate/complex. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. MPEP 2144.05.
Basnakian discloses the compositions may be in variety of dosage forms, such as tablet , capsule, reconstitutable powder, liquids, shake, etc. and the compositions may be incorporated into a food product or powder for mixing with a liquid, or administered orally (See [0076]) (which reads on drinkable liquid of instant claim 26).
Basnakian discloses molar ratio of aminothiol drug/ zinc is about 2:1 to about 1:1 (See [0055], Table 4, claim 4). Basnakian explicitly teaches the molar ratio of Zn-Cysteamine (ZnxLy(H2O)z, wherein cysteamine / zinc is about 2: 1 (X=1, Y=2) (which read on instant claim 22, 46).
Basnakian discloses dose /amount of agent vary depending on the treatment, subject, etc. and can be determined by a skilled artisan following treatment guidelines. Basnakian teaches orally administration amount at about 0.01g to about 2.5 g (See [0105]-[0106])(which reads on instant claims 27).
Basnakian collectively teaches pharmaceutical composition comprising aminothiol compound (e.g. cysteamine.), zinc salt (e.g. zinc chloride, zinc acetate, etc.) and pharmaceutical acceptable excipients.
Basnakian is silent about the Zn- aminothiol chelate/complex enhancing stability of cysteamine and/or improving odor taste of cysteamine as recited in instant claims 43 and 45. However, stabilizing cysteamine and improving its odor/taste is the direct result/intrinsic property of forming Zn-cysteamine complex/chelate. A skilled artisan would have known aminothiol compound (cysteamine) having free SH group is unstable and easily oxidized and has unpleasant odor. As indicated by Shu (2016), thiol group of cysteamine and zinc chloride forms coordinate bond within the cysteamine/Zn chelate/complex which reduce the oxidation of thiol group and would provide improved stability of cysteamine and mask the unpleasant odor of sulfur.
Basnakian is silent about ophthalmic liquid limitation recited in claims 24-25, 38 and 48. CYSTARAN® is cysteamine ophthalmic solution containing 6.5 mg/mL (0.65% w/v) of cysteamine hydrochloride equivalent to 4.4 mg/mL of cysteamine (0.44%), indicated for the treatment of corneal cystine crystal accumulation in patients with cystinosis(which reads on instant claim 24-25).
Longo teaches ophthalmic formulation of cysteamine for treating cystinosis with pH from 4.0-5.0, comprising gelatinous system wherein the gelatinous system comprising zinc (See Col. 4, lines 45-47, 60; Examples 1-4; Formulation 1; Col.9, lines 20-24; claim 1)(which reads on instant claim 50).
Pescina teaches ocular delivery of cysteamine is challenging for its poor permeability and stability in solution and teaches the impact of pH and pharmaceutical excipients (e.g. NaCl, EDTA, benzalkonium chloride BAC) on the stability in solution of cysteamine (See whole article). Pescina teaches cysteamine hydrochloride (0.44% free base) in variety combination with different excipient and stability study at pH 4.2 to 7.4 (See Tables 1-3; page 175, left column; 3.2 stability study).
It would have been obvious and logical for one of ordinary skill in the art before the effective filing date of instant application to incorporate cysteamine-Zn complex taught by Basnakian in more dosage form of cysteamine including ophthalmic liquid, oral administration, or parenteral dosage, etc. based on the combined teachings of Basnakian, Shu, CYSTARAN® label and Longo, together with exploration/optimization based on Pescina and general knowledge of cysteamine formulation, and arrive at instantly claimed application with reasonable expectation of success. At the time instant invention was made, it was already known pharmaceutical composition comprising zinc-chelate of aminothiol (e.g. cysteamine) and zinc salt (e.g. zinc chloride) and pharmaceutical acceptable excipients could be made in a variety of dosage forms(e.g. aqueous solution) as taught by Basnakian. A skilled artisan would also know cysteamine/Zn chelate/complex protects/reduces the oxidation of thiol group which would provide improved stability of cysteamine and mask the unpleasant order of sulfur as indicated by Shu. It was also known that cysteamine can be administered in ophthalmic liquid as taught by CYSTARAN® label and Longo, A skilled artisan would also know to experiment/optimize pH and other excipients as taught by Pescina and general knowledge of cysteamine formulation. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. MPEP 2144.05.
A person of ordinary skill in the art would be motivated to further explore cysteamine-Zn complex in other dosage form of cysteamine (e.g. ophthalmic eye drop) because cysteamine-Zn complex would improve the stability and/or taste of cysteamine as indicated by Shu, and Basnakian teaches zinc chelates of aminothiols have dual cytoprotective effects and better cytoprotection than the ligand. The combined teachings of prior art, together with exploration/optimization based on general knowledge of pharmaceutical formulation of thiol drug would provide a pharmaceutical composition (e.g. ophthalmic eye drop) comprising cysteamine/ zinc complex with enhanced stability at desirable pH without unpleasant odor for treating cystinosis.
One of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention based on the combined teachings of prior art, together with exploration/optimization based on general knowledge of thiol drug , metal-chelate and pharmaceutical formulation. Therefore, the invention as a whole is 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.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (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 LIYUAN MOU whose telephone number is (571)270-1791. The examiner can normally be reached Mon-Fri 9:00-5:30.
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/LIYUAN MOU/Examiner, Art Unit 1628
/JARED BARSKY/Primary Examiner, Art Unit 1628
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