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 .
Amendments & Claim Status
The amendment to the claims filed 04 May 2026 is acknowledged and entered.
Claims 1-3, 5-9, 11-14, and 16-17 are amended.
Claims 18-20 are newly added.
Claims 1-20 are pending.
Response to Arguments
Applicant arguments, filed 04 May 2026, with respect to the rejections under 101, 112(b), 102, and 103 have been fully considered.
With respect to the rejection of claims 7-10 under 35 USC 101 because the claimed invention is directed to a natural phenomenon without significantly more, Applicant’s arguments have been fully considered and are persuasive.
Applicant argues the amendments to claim 7, specifically the added phrases which recite the composition is “formulated for ocular administration for reducing myopia progression” and the composition further comprises “a pharmaceutically acceptable carrier comprising beta-cyclodextrin (β-CD), wherein the beta-cyclodextrin (β-CD) forms a complex with the compound”, moot the rejection as amended claim 7 is subject-matter eligible (Remarks, p. 7-8).
Since amended claim 7 recites the compound, celastrol, forms a complex with β-CD, Examiner agrees this additional element renders amended claim 7 as significantly more than the judicial exception because, to the Examiner’s knowledge, celastrol does not form a complex with β-CD in nature.
The rejection of claims 7-10 of 05 February 2026 under 101 is withdrawn.
With respect to the rejection of claims 11-12 under 35 USC 112(b) as being indefinite, Applicant’s arguments have been fully considered and are persuasive. Amendments moot the rejection of claims 11-12.
The rejection of claims 11-12 of 05 February 2026 under 112(b) is withdrawn.
With respect to the rejection of claims 7-10 under 35 USC 102(a)(1) as being anticipated by L. Guo (Guo et al., Biomaterials Science, 2021, 9, 6355-6380), Applicant’s arguments have been fully considered and are persuasive.
Applicant argues L. Guo does not disclose the composition containing celastrol and β-CD as recited by amended claim 7 and, as such, L. Guo does not anticipate amended claim 7 (Remarks, p. 8-9).
Since amended claim 7 recites the compound, celastrol, forms a complex with β-CD, Examiner agrees this additional element renders amended claim 7 as unanticipated by L. Guo because L. Guo does not disclose β-CD nor a composition comprising β-CD and celastrol. Thus, Amendments moot the rejection of claims 7-10 under USC 102(a)(1).
The rejection of claims 7-10 of 05 February 2026 under 102(a)(1) is withdrawn.
With respect to the rejection of claims 1-4 under USC 103 as being unpatentable over Thomson (Thomson et al., Experimental Eye Research, 2020, 200, 108233) in view of H. Guo (Guo et al., ACS Chemical Biology, 2022, 17(8), 2003-2009; IDS dated 24 Feb. 2025, Cite No. 2), Applicant’s arguments have been fully considered and are not persuasive. Note the claims have been amended and therefore require new grounds of rejection. Accordingly, the previous rejection under 35 U.S.C. 103 is mooted by the amendments and is withdrawn. The responses herein are with respect to Applicant’s arguments in view of the amendments and are intended to clarify the record and support the new grounds of rejection.
Regarding Thomson, Applicant argues Thomson does not teach reducing myopia progression using celastrol and, as such, provides no guidance in regard to formulating a hydrophobic, stability-limited natural product like celastrol for safe and effective administration. Additionally, Applicant argues Thomson does not teach celastrol in complex with β-CD.
Regarding H. Guo, Applicant argues H. Guo does not cure the deficiencies of Thomson because H. Guo studied celastrol in neuroendocrine chromaffin cells, does not study celastrol in ocular tissues (i.e., vitreous, cornea, or conjunctiva), and contains no suggestion their findings regarding the ability of celastrol to increase dopamine by inhibiting COMT would apply to other cell types. Additionally, Applicant argues H. Guo provides no guidance in regard to formulating a hydrophobic, stability-limited natural product like celastrol for safe and effective administration and does not teach celastrol in complex with β-CD.
Additionally, Applicant argues the instant Specification discusses the uncertainty in administering celastrol due to its side effects when administered in high doses, limited bioavailability, undesired biodistribution, poor water solubility, and narrow therapeutic ranges.
Since H. Guo identifies celastrol as a catechol-O-methyltransferase inhibitor (COMT), a skilled artisan would have expected celastrol to have an inhibitory effect on COMT in any tissue types wherein COMT is expressed, including ocular tissues. As evidenced by Waltman (Waltman et al., “Catechol-O-methyltransferase and monoamine oxidase activity in the ocular tissues of albino rabbits”, Investigative Ophthalmology & Visual Science, 1964, Vol. 3, p. 601-605.), COMT activity was observed in rabbit ocular tissues (p. 603, Fig. 1 and Table 1). Thus, a skilled artisan would have had a reasonable expectation of success in increasing dopamine levels in the eye by inhibiting COMT because COMT had been shown to be present in ocular tissues. Furthermore, as stated in the rejection of 05 February 2026, “…Thomson teaches myopia may be attenuated in chicks by administering… dopamine…” (p. 6, ¶ 11). Thus, a skilled artisan would have expected increasing dopamine levels in the eye by administering a COMT inhibitor, as opposed to dopamine, would reduce myopia progression.
With respect to the rejection of claims 5-12 under USC 103 as being unpatentable over Thomson (Thomson et al., Experimental Eye Research, 2020, 200, 108233) in view of H. Guo (Guo et al., ACS Chemical Biology, 2022, 17(8), 2003-2009; IDS dated 24 Feb. 2025, Cite No. 2) as evidenced by Faust (Faust et al., BMC Neuroscience, 2009, 10(109); IDS dated 24 February 2025, Cite No. 1), Applicant’s arguments have been fully considered and are not persuasive. Note the claims have been amended and therefore require new grounds of rejection. Accordingly, the previous rejection under 35 U.S.C. 103 is mooted by the amendments and is withdrawn. The responses herein are with respect to Applicant’s arguments in view of the amendments and are intended to clarify the record and support the new grounds of rejection.
Regarding Faust, Applicant argues Faust does not teach celastrol in complex with β-CD and the combination of Thomson, H. Guo, and Faust does not provide any teaching or suggestion to improve the solubility, stability, and permeation of a celastrol composition formulated for ocular administration.
Examiner agrees the combination of Thomson, H. Guo, and Faust does not teach a complex comprising celastrol and β-CD. Accordingly, additional prior art (Yang et al., “Preparation, characterization and cytotoxic evaluation of inclusion complexes between celastrol with polyamine-modified β-cyclodextrins,” Journal of Inclusion Phenomena and Macrocyclic Chemistry, (2019), Vol. 95, p. 147-157.), which teaches celastrol in complex with β-CD, has been added to the new 103 rejection outlined below.
With respect to the rejection of claims 13-17 under USC 103 as being unpatentable over Thomson (Thomson et al., Experimental Eye Research, 2020, 200, 108233) in view of H. Guo (Guo et al., ACS Chemical Biology, 2022, 17(8), 2003-2009; IDS dated 24 Feb. 2025, Cite No. 2) and further in view of Zhou (CN114796205A), Applicant’s arguments have been fully considered and are not persuasive. Note the claims have been amended and therefore require new grounds of rejection. Accordingly, the previous rejection under 35 U.S.C. 103 is mooted by the amendments and is withdrawn. The responses herein are with respect to Applicant’s arguments in view of the amendments and are intended to clarify the record and support the new grounds of rejection.
Regarding Zhou, Applicant argues Zhou does not disclose, teach, or suggest either celastrol or β-CD and does not mention the composition is formulated for ocular administration. Furthermore, Applicant argues, the combination of Thomson, H. Guo, and Zhou does not provide any teaching or suggestion to improve the solubility, stability, and permeation of a celastrol-containing composition to an eye and a person having ordinary skill in the art (PHOSITA) would not have been motivated to combine the teachings of Thomson, H. Guo, and Zhou. Additionally, Applicant alleges a composition containing both celastrol and β-CD produces unexpected therapeutic results due to the enhancement in the composition’s solubility, stability, and permeation in vivo, stating the composition does not precipitate in the vitreous when administered via intravitreal injection. Applicant alleges the data presented in the drawings shows a marked protective effect against myopia progression, specifically by improving the IOD refractive error, axial elongation, and increasing choroidal thickness.
Applicant is correct in stating Zhou does not explicitly disclose, teach, or suggest a composition containing celastrol or β-CD. However, Zhou does teach pharmaceutical compositions for treating myopia and suggests dopamine agonists may be included in the composition. By definition, a dopamine agonist would be expected to have a dopaminergic effect, similar to celastrol as taught by H. Guo. Additionally, Zhou indicates said compositions may be administered intravenously, topically, or intravitreally. Because a drug administered intravitreally is injected directly into the vitreous of the eye, it would necessarily be formulated for ocular administration.
Applicant has not met the burden of unexpected results (MPEP 716.02). As stated in the instant Specification, decreasing choroidal thickness is a known hallmark of myopia progression. Because Thomson discloses increasing dopamine levels in the eye reduces myopia and H. Guo discloses celastrol increases dopamine levels, a prima facie case is made that a PHOSITA would have expected increasing dopamine levels indirectly using celastrol, as opposed to increasing dopamine levels directly using dopamine, would reduce myopia and this reduction in myopia would have been expected to be marked by a decrease in choroidal thickness. Thus, although Applicant’s data suggests celastrol administration reduces myopia by increasing ocular dopamine levels, such results would not have been unexpected in view of the prior art. Furthermore, Examiner is unaware of any data which suggests the composition comprising celastrol and β-CD does not precipitate in the vitreous when administered via intravitreal injection compared to a composition comprising celastrol without β-CD.
Specification
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said” should be avoided.
The abstract of the disclosure is objected to because it contains legal phraseology, specifically the term “comprising.” A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
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.
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.
Claims 1-4 are rejected under 35 U.S.C. 103 as being unpatentable over Yang (Yang et al., “Preparation, characterization and cytotoxic evaluation of inclusion complexes between celastrol with polyamine-modified β-cyclodextrins,” Journal of Inclusion Phenomena and Macrocyclic Chemistry, (2019), Vol. 95, p. 147-157.) in view of Thomson (Thomson et al., Experimental Eye Research, 2020, 200, 108233) and H. Guo (Guo et al., ACS Chemical Biology, 2022, 17(8), 2003-2009; IDS dated 24 Feb. 2025, Cite No. 2).
Regarding claims 1-4, Yang teaches complexes comprising celastrol and β-cyclodextrins, specifically mono polyamine-modified β-CD (H1) and polyamine-bridged bis(β-CD) (H2) (p. 147, Abstract). Yang notes celastrol’s use in medicine has been limited due to its poor solubility, low bioavailability, and toxicity (p. 148, ¶ 1). To help overcome these problems, Yang prepares complexes comprising celastrol and β-CDs and demonstrates said complexes display improved solubility and reduced toxicity, suggesting celastrol-β-CD complexes are more suitable for clinical applications than celastrol alone (p. 155, Conclusion). Additionally, Yang describes dissolving celastrol in DMSO (p. 150, Col. 2, Cytotoxicity assay).
Yang does not explicitly teach reducing myopia progression using celastrol.
Thomson teaches myopia may be attenuated in chicks by administering dopaminergic compounds, including dopamine and levodopa, to the animals as topical eye drops and/or intravitreal injections (Abstract, Paragraph 4; p. 1, Col. 2; Conclusions). Thomson compares these administration routes, stating topically administered compounds achieve less penetration into the eye compared to intravitreally applied compounds (p. 8, Col. 2, Bottom Paragraph) and, as a result, applying dopamine topically was less successful in preventing myopia than applying it via intravitreal injections (Figs. 1-2). To achieve greater success in myopia-prevention using topically-applied dopamine, Thomson mentions utilizing penetrating agents such lipid-based carriers (p. 8, Col. 2, Final Complete Sentence).
Thomson does not explicitly teach reducing myopia progression using celastrol in a complex with β-CD.
H. Guo reveals celastrol acts as a catechol-O-methyltransferase (COMT) inhibitor (Title; Abstract; p. 2003, Col. 2, Bottom Paragraph). H. Guo discloses COMT inhibitors have been used in combination with levodopa to alleviate Parkinson’s disease symptoms (p. 2003, Col. 2, Second Sentence). Furthermore, H. Guo shows treating cells with celastrol increases dopamine levels (Abstract, Third Sentence; Fig. 4. C). Thus, while celastrol is not classified as a dopaminergic compound, it exhibits neuroprotective activity and increases dopamine levels.
H. Guo does not explicitly teach reducing myopia progression using celastrol in a complex with β-CD.
Prior to the filing of the instant application, a person having ordinary skill in the art (PHOSITA) following the teachings of Yang would have found it prima facie obvious to use a celastrol complexed with β-CD in treating myopia based on the teachings of Thomson and H. Guo because Thomson shows increasing dopamine levels in the eye prevents myopia, H. Guo teaches celastrol can increase dopamine levels by inhibiting COMT, and Yang teaches celastrol has improved pharmaceutical properties when complexed with β-CD. Thus, a PHOSITA would have had a reasonable expectation of success in using celastrol in complex with β-CD to increase dopamine levels in the eye, thereby attenuating myopia symptoms.
Claims 5-12 and 18-20 are rejected under 35 U.S.C. 103 as being unpatentable over Yang (Yang et al., “Preparation, characterization and cytotoxic evaluation of inclusion complexes between celastrol with polyamine-modified β-cyclodextrins,” Journal of Inclusion Phenomena and Macrocyclic Chemistry, (2019), Vol. 95, p. 147-157.) in view of Thomson (Thomson et al., Experimental Eye Research, 2020, 200, 108233) and H. Guo (Guo et al., ACS Chemical Biology, 2022, 17(8), 2003-2009; IDS dated 24 Feb. 2025, Cite No. 2) as evidenced by Faust (Faust et al., BMC Neuroscience, 2009, 10(109); IDS dated 24 February 2025, Cite No. 1).
Regarding claims 5-12 and 18-20, Yang in view of Thomson and H. Guo teaches all of the elements of the claimed invention as stated above. Furthermore, Thomson teaches administering at least 150 µM dopamine to chickens as a single intravitreal injection over four consecutive days (p. 3, First Complete Sentence; Table 2). Thomson suggests topically administering dopaminergic compounds may be a useful approach to treating human myopia (p. 8, Col. 2, First Complete Paragraph, Last Sentence).
Furthermore, H. Guo (citing Faust), states celastrol has displayed dopaminergic neuroprotection in a Drosophila melanogaster Parkinson’s disease model (p. 2003, Col. 1, Paragraph 2, Sentence 4).
However, Yang, Thomson, and H. Guo do not teach:
Administering 74 µM celastrol in complex with β-CD (Claim 19), or administering 74 µM celastrol in complex with β-CD celastrol to a chicken once daily via intravitreal injection over four consecutive days (Claim 5).
Administering 1.665 µM celastrol in complex with β-CD (Claim 20), or administering 1.665 µM celastrol in complex with β-CD to a human once daily via an eyedrop (Claim 6).
Administering about 0.1-10 mM celastrol in complex with β-CD (Claim 18).
Faust discloses celastrol protects against the loss of dopamine in a D. melanogaster Parkinson’s disease model.
It would have been prima facie obvious to a PHOSITA before the effective filing date of the claimed invention to have optimized the celastrol administration route and therapeutically effective concentration to achieve the desired reduction in myopia progression in chickens and in humans (MPEP 2144.05(II)). Thomson discloses a method wherein a drug intended to reduce myopia progression by increasing dopamine in the eye is administered to chickens via intravitreal injection. H. Guo teaches celastrol inhibits COMT, which leads to increased dopamine levels. Thus, a PHOSITA would have been motivated to increase dopamine levels in a myopia animal model via intravitreal celastrol administration in order to reduce myopia symptoms and would have been able to optimize the celastrol dose through routine experimentation. Furthermore, animal models are used in biomedical research to study diseases impacting humans. Thomson teaches dopaminergic compounds as potentially useful in treating human myopia and suggests topical administration as a potential administration route. Faust discloses celastrol can help reduce dopamine depletion, which is a characteristic of celastrol due to its chemical structure. Thus, a PHOSITA would have been motivated to attempt to reduce myopia progression in humans using eyedrops containing celastrol and optimized the celastrol dose through routine experimentation to achieve the desired reduction in myopia symptoms.
Claims 13-17 are rejected under 35 U.S.C. 103 as being unpatentable over as being unpatentable over Yang (Yang et al., “Preparation, characterization and cytotoxic evaluation of inclusion complexes between celastrol with polyamine-modified β-cyclodextrins,” Journal of Inclusion Phenomena and Macrocyclic Chemistry, (2019), Vol. 95, p. 147-157.) in view of Thomson (Thomson et al., Experimental Eye Research, 2020, 200, 108233) and H. Guo (Guo et al., ACS Chemical Biology, 2022, 17(8), 2003-2009; IDS dated 24 Feb. 2025, Cite No. 2) and further in view of Zhou (CN114796205A).
Regarding claims 13-15, Yang, Thomson, and H. Guo teach all of the elements of the claimed subject matter except applying celastrol directly to the vitreous, cornea, or conjunctiva of the subject to increase choroidal thickness of a uvea. Furthermore, as discussed above, a PHOSITA would have had a reasonable expectation of success in combining the teachings of Yang, Thomson, and H. Guo to conclude celastrol complexed with β-CD would have been likely to reduce myopia progression.
With respect to claims 13-15, the combination of Yang, Thomson, and H. Guo fails to teach increasing choroidal thickness by administering a drug directly to a subject’s vitreous, cornea, or conjunctiva.
Zhou presents methods and pharmaceutical compositions intended to lessen myopia and its related symptoms using bendazac lysine or bendazac (Paragraph [n0029]). Zhou teaches the pharmaceutical composition may also comprise other drugs, such as dopamine agonists (Paragraphs [n0029], [n0088], and [n0091]). Furthermore, Zhou discloses various administration routes including oral administration, intravenous administration, topical administration, and intravitreal injection (Paragraphs [n0019] and [n0078]) and the subject can be a human experiencing myopia symptoms (Paragraph [n0084]) or animals including sheep and horses (Paragraph [n0104]). Zhou discloses the myopia-prevention composition may include ophthalmologically acceptable carriers (Paragraphs [n0110], [n0112], and [n0113]). Finally, Zhou discloses bendazac lysine and bendazac increase choroidal thickness and/or inhibit a decrease in choroidal thickness in myopic individuals (Paragraphs [n0036], [n0044]). As stated in the instant specification (Paragraph [0046]), decreasing choroidal thickness is a known hallmark of myopia progression. Finally, Zhou discloses administering the myopia-prevention composition topically to the cornea (Paragraphs [n0019], [n0078]) and by subconjunctival injection (Paragraphs [n0282], [n0291], [n0301], [0308], and [n0311]).
It would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date of the claimed invention to have modified Yang and Thomson to incorporate the teachings of H. Guo and Zhou. As discussed above, combining Thomson’s teachings that increasing dopamine levels in the eye reduces myopia and H. Guo’s teachings that celastrol increases dopamine levels to predict celastrol would reduce myopia progression would have been obvious to a PHOSITA. Furthermore, Zhou teaches administering a drug intended to reduce myopia in humans increases choroidal thickness and may be applied topically to the cornea or injected into the conjunctiva. Thus, it would have been obvious to substitute the bendazac taught by Zhou with celastrol.
Regarding claims 16-17, Zhou discloses intravitreal injections and subconjunctival injections are means by which a drug intended to reduce myopia may be applied to the eye (Paragraphs [n0019] and [n0282]).
It would have been prima facie obvious to a PHOSITA before the effective filing date of the instant application to have optimized the celastrol administration route and therapeutically effective concentration to achieve the desired reduction in myopia progression in chickens and in humans (MPEP 2144.05(II)). Each drug administration route exhibits unique advantages and disadvantages, as Thomson discloses continuous intravitreal injections have a negative impact on myopia symptoms which makes eyedrops more viable over a longer time period (p. 2, Col. 1). Furthermore, the celastrol dose could have been optimized by a PHOSITA to achieve a desired reduction in myopia while also mitigating any celastrol toxicity, which has been disclosed by L. Guo (p. 6372, Col. 1, Section 3).
Conclusion
Claims 1-20 are rejected.
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 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.
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/B.L.B./Examiner, Art Unit 1623
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
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