18501136
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 .
Status of the Claims
The listing of claims filed 03 November 2023 has been examined. Claims 1-17 are pending.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 24 February 2025 is acknowledged and has been considered.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 7-10 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon without significantly more.
Claim 7 recites a naturally occurring compound. This judicial exception is not integrated into a practical application because the claim requires nothing beyond the naturally occurring composition itself. The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception because only the presence of the compound is required by the claim. Furthermore, the claim recites an intended use and does not affirmatively recite an action that effects a particular treatment for myopia progression.
The courts have emphasized that to show a marked difference, a characteristic must be changed as compared to nature, and cannot be an inherent or innate characteristic of the naturally occurring counterpart or an incidental change in a characteristic of the naturally occurring counterpart (Myriad, 133 S. Ct. at 2111, 106 USPQ2d at 1974-75). Thus, in order to be markedly different, Applicant must have caused the claimed product to possess at least one characteristic that is different from that of the naturally occurring counterpart. If there is no or only incidental changes in any characteristic, the claimed product lacks markedly different characteristics and is a product of nature exception.
Claim 7 recites a composition comprising the compound celastrol. Celastrol is known to be present in naturally occurring Trypterygium wilfordii, which is also called “thunder god vine,” and has been acknowledged as a promising traditional medicine in pharmaceutical development (Corson et al., p. 769; p. 771-772; Fig. 1). The instant specification presents no evidence that celastrol as recited in the instant claims results in any markedly different characteristics compared to its natural state. The claimed compound, then, comprises a naturally occurring bioactive chemical which is unchanged from its natural state. Accordingly, the claims are drawn to the natural product judicial exception to patentable subject matter.
Next, the claims are evaluated to determine whether any additional elements or a combination of elements is sufficient to render the claim significantly more than the judicial exception. In this case, the additional elements recited in dependent claims 8-12 pertain to celastrol administration routes, compositions comprising celastrol and a pharmaceutically acceptable carrier, and administering celastrol to animals. Firstly, in claim 8 the “being administered” claim language is an intended use that adds no structural features to the composition and intravitreal and intravenous injections as well as oral and topical administrations are each well-known, routine, and conventional administration routes in the pharmaceutical field (MPEP 2106.05). Additionally, the broadest reasonable interpretation would encompass administering celastrol in any disease. Secondly, drug compositions that include a pharmaceutically acceptable carrier are well-known, routine, and conventional within pharmaceutical development. No evidence is presented in the instant specification to imply the claimed compositions result in any markedly different characteristics to the innate or inherent characteristics of celastrol. Third, merely intending to apply celastrol, or a specified amount thereof, to an animal via routine methods does not result in patent-eligible subject matter (MPEP 2106.05). These product claims lack any limitations which limit the scope to a particular disease or patient population. Thus, the claims are drawn to a judicial exception and lack additional elements transforming the claimed subject matter into patent-eligible subject matter.
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 11-12 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. The claims recite “amount” indicating that they are limited by quantity and “mM” units indicating they are limited by concentration. Based on these conflicting recitations, the metes and bounds of the claimed subject matter are unclear to a person having ordinary skill in the art.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 7-10 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Guo et al., Biomaterials Science, 2021, 9, 6355-6380, hereinafter L. Guo.
L. Guo reviews approaches by which celastrol, a compound extracted from T. wilfordii bark (p. 6355, Col. 1), can be packaged in various nanocarriers to improve its pharmaceutical characteristics including improving its oral bioavailability and reducing toxicity (p. 6356, Col. 1; p. 6372, Col. 1, Section 3). Additionally, L. Guo discusses the benefits and/or drawbacks associated with each nanocarrier as well as some diseases and administration routes in which nanocarriers have been studied.
Regarding claims 7-10, L. Guo indicates celastrol, (Fig. 1) can be administered to animal models, like rats and rabbits, via multiple routes including oral, intravenous, and topical administration (Table 2). Furthermore, L. Guo discusses numerous celastrol-containing nanocarriers such as micelles, dendrimers, liposomes, and polymeric nanoparticles (p. 6356, Col 1, Paragraph 1; Fig. 2).
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.
Claim 1-4 are rejected under 35 U.S.C. 103 as being unpatentable over Thomson et al., Experimental Eye Research, 2020, 200, 108233 in view of Guo et al., ACS Chemical Biology, 2022, 17(8), 2003-2009 (IDS dated 24 Feb. 2025, Cite No. 2).
Regarding claims 1-4, 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).
However, Thomson does not teach reducing myopia progression using celastrol.
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.
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 Thomson to incorporate the teaching of H. Guo that celastrol increases dopamine levels in cells. Because Thomson shows increasing dopamine levels in the eye prevents myopia, a PHOSITA would have had a reasonable expectation of success in administering a drug that causes an increase in dopamine levels to reduce myopia progression.
The evidence provided in the instant specification has been considered, but it is insufficient to overcome the prima facie case of obviousness. While the group given 74 µM celastrol displayed a 46.3% decrease in refractive errors relative to the vehicle group (Instant Application, Fig.2A), Thomson suggests a similar result may be achieved by treating chicks with 150-0.150 mM intravitreal dopamine (Table 2, Fig. 1B) or D4 dopamine (Fig. 1D). For example, Thomson reports the animals that received 0.150 mM dopamine, which is equal to about 0.002 µmoles (Table 2), had a measured refraction of about 0.19D as opposed to about -0.80D in the group that received vehicle injections (Table 3, Fig. 1B). By the Examiner’s calculation, this change amounts to approximately a 123.8% change in refraction. Because Thomson teaches injecting dopamine into the eye to achieve an increase in dopamine levels and the instant application recites administering celastrol to the eye to accomplish the same, these percentages cannot be directly compared. However, Thomson does illustrate increasing dopamine levels in the eye had been known to result in a decrease in refraction. Furthermore, Thomson shows the group which received 1.500 µmoles of dopamine per day, which is equal to about 150 mM (Table 2), experienced a decrease in axial length compared to the vehicle group (Fig. 1A). Thomson reports axial length in the animals that received only vehicle injections to be about 9.13 and the axial length in the animals that received 1.500 µmoles dopamine to be about 8.76 (Table 3). By the Examiner’s calculation, this change amounts to approximately a 4% decrease in axial length. As previously stated, since Thomson teaches injecting the eye with dopamine to increase its dopamine levels as opposed to using celastrol, this is not a direct comparison. However, this does demonstrate that increasing dopamine levels within the eye would have been expected to decrease axial length. Applicants may provide objective data to overcome the prima facie case of obviousness established here. For example, Applicants may set forth unexpected results as set forth in MPEP 716.02.
Claims 5-12 are rejected under 35 U.S.C. 103 as being unpatentable over Thomson in view of H. Guo as evidenced by Faust et al., BMC Neuroscience, 2009, 10(109) (IDS dated 24 February 2025, Cite No. 1), hereinafter Faust.
Regarding claims 5-6, Thomson in view of 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, Thomason and H. Guo do not teach:
Administering 74 µM celastrol to a chicken once daily via intravitreal injection over four consecutive days, as described by claim 5.
Administering 1.665 µM celastrol to a human once daily via an eyedrop, as described by claim 6.
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 an inherent 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 Thomson in view of H. Guo as applied to claims 1-6 and 11-12 above, and further in view of CN114796205A, hereinafter Zhou.
Regarding claims 13-15, 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 Thomson and H. Guo to conclude celastrol would have been likely to reduce myopia progression.
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 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
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/B.L.B./
Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623