DETAILED ACTION
Notice of 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
Claims 1-20 are currently pending and are the subject of this Office Action. This is the first Office Action on the merits of the claims.
Priority
The instant Application was filed 4/28/2023, claiming priority to 10/29/2021 as CIP of PCT/KR2021/15441 which, in turn, claims priority to 10/29/2020 based on the prior filed application KR 10-2020-0142465.
However, PCT/KR2021/15441 and KR 10-2020-0142465 are not in English, rendering it impossible to determine the priority of the instantly claimed invention.
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.
Claims 15-17 are rejected under 35 U.S.C. 101 because the claimed recitation of a use (i.e., “for administration” (claim 15), “for the prevention or treatment of ischemic optic neuropathy” (claim 16), and/or “for the prevention or treatment of glaucoma” (claim 17)), without setting forth any steps involved in the process, results in an improper definition of a process, i.e., results in a claim which is not a proper process claim under 35 U.S.C. 101. See for example Ex parte Dunki, 153 USPQ 678 (Bd.App. 1967) and Clinical Products, Ltd. v. Brenner, 255 F. Supp. 131, 149 USPQ 475 (D.D.C. 1966).
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(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 1-20 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention
Claim 1 is drawn to “[a]n ophthalmic formulation in the form of an eye drop comprising an inclusion complex of a poorly water-soluble drug… entrapped in cyclodextrin or a cyclodextrin derivative in an aqueous solution of pH 10 or higher”.
Yet, claim 6 is drawn to the ophthalmic formulation of claim 1 which is prepared by a solubilization method comprising the steps of mixing an aqueous solution comprising the cyclodextrin or cyclodextrin derivative having a pH of at least 10 with a solution comprising the poorly water-soluble drug, and then carrying out “a pH adjusting step of mixing a pH adjusting agent into the solution”.
And, claim 12 recites “[t]he ophthalmic formulation of claim 1, wherein the pH is between 5 and 9”.
The claims are indefinite because the pH of the ophthalmic formulation in the form of an eye drop is unclear.
In the interest of compact prosecution, it is understood that the pH of the ophthalmic formulation in the form of an eye drop as recited by claims 1 and 6 is not defined. Rather, claims 1 and 6 merely define the pH of the aqueous solution in which the inclusion complex is formed, and which can adjusted, for example, to “between 5 and 9” as recited by claim 12 by carrying out “a pH adjusting step of mixing a pH adjusting agent into the solution” as recited by claim 6.
Claims 14-15 is drawn to “[a] pharmaceutical composition comprising an inclusion complex, wherein [a] poorly soluble drug… is entrapped within 2-hydroxypropyl-β-cyclodextrin in an aqueous solution of pH 10 or higher” (claim 14), more specifically “for administration as an ophthalmic formulation in the form of an eye drop” (claim 15).
For the same reasons as discussed above regarding claim 1, the claims are indefinite because the pH of the ophthalmic formulation in the form of an eye drop is unclear. In the interest of compact prosecution, it is understood that claims 14 and 19 define the pH of the aqueous solution in which the inclusion complex is formed, whereas the pH of the ophthalmic formulation in the form of an eye drop as recited by claims 15-17 and 20 is not defined.
Claim 5 is ADDITIONALLY rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 1 is drawn to an ophthalmic formulation comprising “a poorly water-soluble drug of Formula 1”.
Claim 5 is drawn to “[t]he ophthalmic formulation of Claim 1, wherein the poorly soluble drug of Formula 1 is a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof”.
Claim 1 does not provide support for “a pharmaceutically acceptable salt” of Formula 1, as recited by claim 5 and, as such, claim 5 lacks antecedent basis in claim 1.
Claim 9 is ADDITIONALLY rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 9 is drawn to the ophthalmic formulation where the poorly water-soluble drug is dissolved in the cyclodextrin “in a weight ratio of 1:10 to 40 of the compound… and the” cyclodextrin.
It is unclear whether the weight ratio of poorly water-soluble drug to cyclodextrin ranges from 1:10 to 1:40 or from 1:10 to 40:1.
In the interest of compact prosecution, it is understood that the weight ratio of poorly water-soluble drug to cyclodextrin ranges from 1:10 to 40:1
Claims 15-17 are ADDITIONALLY rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claims 15-17 are directed to a pharmaceutical composition “for administration” (claim 15), “for the prevention or treatment of ischemic optic neuropathy” (claim 16), and/or “for the prevention or treatment of glaucoma” (claim 17).
However, since the claims do not set forth any steps involved in the method/process, it is unclear what method/process applicant is intending to encompass. A claim is indefinite where it merely recites a use without any active, positive steps delimiting how this use is actually practiced.
Claim 5 is rejected under 35 U.S.C. 112(d) as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 1 is drawn to an ophthalmic formulation comprising “a poorly water-soluble drug of Formula 1”.
Claim 5 is drawn to “[t]he ophthalmic formulation of Claim 1, wherein the poorly soluble drug of Formula 1 is a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof”.
Claim 1 does not provide support for “a pharmaceutically acceptable salt” of Formula 1, as recited by claim 5 and, as such, claim 5 fails to further limit claim 1.
Applicant may cancel the claim, amend the claim to place the claim in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
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.
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 1-20 are rejected under 35 U.S.C. 103(a) as being unpatentable over Choi et al (Biochem Pharmacol 169:113632, 11 pages, September 5, 2019) in view of Abelson et al (Review of Ophthalmology, 2017) and Bae et al (KR 2017-0022598, based on the attached Machine Translation).
Claims 1 and 5 are drawn to an ophthalmic formulation in the form of an eye drop (more specifically, wherein the pH is between 5 and 9 (claim 12)) comprising an inclusion complex of a poorly water-soluble drug of Formula 1 entrapped in a cyclodextrin or a cyclodextrin derivative in an aqueous solution of pH 10 or higher, allowing it to pass through the corneal epithelium and be delivered into ocular tissue, wherein:
(a) the poorly water-soluble drug of Formula 1 is 4-(2-(6-(2,6-dichloro-4-(trifluoromethyl)phenyl)-4-methyl-1,1-dioxido-1,2,6-thiadiazinan-2-yl)acetamido)adamantane-1-carboxide, aka KR-67607 (claim 13) having the following structure:
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; and
(b) the cyclodextrin or cyclodextrin derivative is 2-hydroxypropyl-β-cyclodextrin, aka HPβCD (claim 4).
Choi et al teach an ophthalmic formulation in the form of an eye drop comprising KR-67607 (see, e.g., Page 3, Figure 1A and Page 3, Section 2.5 “[d]rugs were administered topically (one drop…) twice a day”), specifically disclosing “using KR-67607 in eye drops for long-term treatment to inhibit acute or continuous glaucoma development” (Page 10, Column 2).
However, Choi et al do not teach the compound as an inclusion complex, entrapped in 2-hydroxypropyl-β-cyclodextrin, in an aqueous solution of pH 10 or higher as claimed.
Yet, it is evident that KR-67607, which has a low logS and high cLogP (as demonstrated, for example, by ChemDraw (not currently available to the USPTO)) has low solubility in water.
And, as taught by Abelson et al, “[s]olubility enhancement is an important strategy when developing ophthalmic medications. Many drugs are poorly soluble in water, and substances must be added to increase solubility, raise the therapeutic concentration, and improve bioavailability”
Significantly, Bae et al teach that an “aqueous solution… for treating a dry eye syndrome” (Abstract) comprising the “poorly water-soluble drug” rebamipide (Paragraph 6) can be formulated by “dissolving rebamipide… cyclodextrin or a derivative thereof and a base into water to obtain a solution having pH of 8.5 or more” (Abstract, step (a)), more specifically, wherein the cyclodextrin is “2-hydroxypropyl-β-cyclodextrin” (Paragraph 14) and “the pH is 8.5 through… pH 10” (Paragraph 13), and then “adjusting the solution obtained… to pH of 7-8.5” (Abstract, step (b)), which exhibits improved bioavailability (Paragraph 37).
Accordingly, in further view of Abelson et al and Bae et al, it would have been prima facie obvious to formulate the KR-67607-containing eye drop of Choi et al as an inclusion complex comprising the KR-67607 entrapped in HPβCD in an aqueous solution of pH 10 or higher, wherein the pH of the eye drop is between 5 and 9. Recognizing that KR-67607 is poorly soluble in water, and further considering that “[s]olubility enhancement is an important strategy when developing ophthalmic medications” (as taught by Abelson et al), it would have been prima facie obvious to do so in order to increase solubility, raise the therapeutic concentration, and improve bioavailability of KR-67607 (based on Bae et al) with a reasonable expectation of success.
As such, claims 1, 4-5 and 12-13 are rejected as prima facie obvious.
Claims 2-3 and 18 are drawn to the ophthalmic formulation of claim 1, wherein a sufficient concentration of the poorly water-soluble drug (i.e., KR-67607) can be delivered into the ocular tissue via the inclusion complex (claim 2), wherein the inclusion complex allows for a sufficient amount of the poorly soluble drug to reach the ocular tissues to prevent cell death due to ischemic injury (claim 3), and/or wherein the poorly water-soluble drug protects the ocular tissue and/or optic nerve by a specified mechanism (claim 18).
While the fact that a certain result or characteristic may occur or may be present in the prior art is not sufficient to establish the inherency of that result or characteristic (In re Rijckaert, 9 F.3d 1531 (Fed. Cir. 1993); see also In re Robertson, 169 F.3d 743 (Fed. Cir. 1999), “[i]nherency may not be established by probabilities or possibilities”), it is well settled that “inherency may supply a missing claim limitation in an obviousness analysis” so long as “the limitation at issue necessarily must be present or the natural result of the combination of elements explicitly disclosed by the prior art” (PAR Pharm., Inc. v. TWI Pharm., Inc. 773 F.3d 1186 (Fed. Cir. 2014)). “If… the disclosure is sufficient to show that the natural result flowing from the operation as taught would result in the performance of the questioned function, it seems to be well settled that the disclosure should be regarded as sufficient” (quoting In re Oelrich, 666 F.2d 578 (C.C.P.A. 1981). Thus, as stated by the court in PAR Pharm., Inc. v. TWI Pharm., Inc., “inherency... is present… when the limitation at issue is the ‘natural result’ of the combination of prior art elements” (Id.). And, as stated by the court in In re Dillon (919 F.2d 688 (Fed. Cir. 1990)), “it is not necessary in order to establish a prima facie case of obviousness… that there be a suggestion in or expectation from the prior art that the claimed [invention] will have the same or similar utility as one newly discovered by applicant”.
While the court in PAR Pharm., Inc. v. TWI Pharm., Inc. further indicates that “the concept of inherency must be limited when applied to obviousness” and “[a] party must… meet a high standard in order to rely on inherency to establish the existence of a claim limitation in the prior art in an obviousness analysis”, it must also be remembered that the U.S. Patent Office is not equipped with analytical instruments to test prior art compositions for the infinite number of ways that a subsequent Applicant may present previously unmeasured characteristics. As such, a prior art disclosure of a product or method “appearing to be substantially identical” to that instantly claimed, and rationale or evidence “tending to show inherency”, shifts the burden to the Applicant to prove otherwise (MPEP 2112 (IV)-(V)). As stated in In re Best, Bolton, and Shaw (562 F2d 1252 (CCPA 1977)), “[w]here… the claimed and prior art products are identical or substantially identical, or are produced by identical or substantially identical processes, the PTO can require an applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his claimed product” (see also In re Fitzgerald 619 F2d 67 (CCPA 1980): the burden is shifted to the applicants to “prove that subject matter shown to be in the prior art does not possess characteristic relied on”).
This is especially true in cases where the newly discovered, inherent limitation is claimed functionally rather than structurally. For example, in In re Kubin (561 F.3d 1351 (Fed. Cir. 2009)), discussing claims drawn to an isolated nucleic acid molecule encoding a polypeptide “wherein the polypeptide binds CD48”, the court stated that there is “no obligation to predicate [an] obviousness finding on factual findings regarding a prior art teaching of [the polypeptide’s] binding to the CD48 protein” – the limitation is “not an additional requirement imposed by the claims on the [polypeptide], but rather a property necessarily present in” the polypeptide. As stated by the court in Santarus, Inc. v. Par Pharm., Inc., 694 F.3d 1344 (Fed. Cir. 2012), “[t]o hold otherwise would allow any formulation – no matter how obvious – to become patentable merely by testing and claiming an inherent property” (discussing claims drawn to methods of administering a active agent “wherein upon oral administration… an initial serum concentration of the [active agent] greater than about 0.1 µg / ml is obtained at any time within about 30 minutes after administration” and further noting that “[t]he initial blood serum concentration resulting from administering [the active agent] is an inherent property of the formulation, and an obvious formulation cannot become nonobvious simply by administering it to a patient and claiming the resulting serum concentrations”).
In the instant case, the claimed and prior art products are substantially identical and it would be expected that the prima facie obvious ophthalmic formulation in the form of an eye drop taught by Choi et al in view of Abelson et al and Bae et al would deliver a sufficient amount of KR-67607 into the ocular tissue which would necessarily prevent cell death due to ischemic injury. As stated in In re Papesch, 315 F.2d 381 (CCPA 1963), “[f]rom the standpoint of patent law, a compound and all its properties are inseparable”.
As such, claims 2-3 and 18 are also rejected as prima facie obvious.
Claim 6 is drawn to the ophthalmic formulation of claim 1 prepared according to a solubilization method comprising the steps:
preparing a first solution in which a solubilization promoter (more specifically, a basic substance (claim 8)) is dissolved in water to obtain a solution having a pH of at least 10;
mixing said first solution with HPβCD to obtain a second solution;
mixing KR-67607 into said second solution to obtain a third solution; and
mixing a pH adjusting agent into said third solution to obtain the ophthalmic formulation.
Applicant is reminded that product-by-process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps (MPEP 2113). As stated by the court in In re Thorpe (777 F.2d 695 (Fed. Cir. 1985), “even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claims is the same or obvious from a product of the prior art, the claim is unpatentable even though the prior art product was made by a different process."
As discussed above, Bae et al teach dissolving the poorly water-soluble drug with “cyclodextrin or a derivative thereof and a base into water to obtain a solution having pH of 8.5 or more” (Abstract, step (a)), more specifically, wherein the cyclodextrin is “2-hydroxypropyl-β-cyclodextrin” (Paragraph 14) and “the pH is 8.5 through… pH 10” (Paragraph 13), and then “adjusting the solution obtained… to pH of 7-8.5” (Abstract, step (b)), which exhibits improved bioavailability (Paragraph 37).
As such, claims 6 and 8 are also rejected as prima facie obvious.
Claim 7 is drawn to the ophthalmic formulation of claim 6, wherein the method further comprises a step of dissolving a buffer, isotonic agent, etc. in the solution.
As further taught by Bae et al, the formulation “additionally may include… buffer agent… isotonising agent” and so on (Paragraph 38).
As such, claim 7 is also rejected as prima facie obvious.
Claim 9 is drawn to the ophthalmic formulation of claim 6, wherein KR-67607 is dissolved in HPβCD in a weight ratio of 1:10 to 40 (which is understood to range from 1:10 to 40:1).
As taught by Bae et al, “[t]he weight ratio of the cyclodextrin about the Rebamipide… is not limited specifically. But preferably the cyclodextrin or the cyclodextrin derivative can be dissolved to the weight ratio of 1.5 of the Rebamipide… through the six-fold” (Paragraph 29), further disclosing using weight ratios of drug:cyclodextrin of 1:3 (Paragraph 47), 1:2.01 (Paragraph 78)
As such, claim 9 is also rejected as prima facie obvious.
Claim 10 is drawn to the ophthalmic formulation of claim 6, wherein KR-67607 is in included in an amount ranging from 0.01 to 1.0% w/v.
As taught by Choi et al, KR-67607 was “administered topically (one drop, 20-25 µl) twice a day… 0.15, 0.75 and 1.5 mg/ml KR-67607” (Page 3, Column 1) which equates to 0.015%, 0.075% and 0.15%.
As such, claim 10 is also rejected as prima facie obvious.
Claim 11 is drawn to the ophthalmic formulation of claim 6, wherein the osmolarity is from 250 to 340 mOsmol.
Bae et al specifically teach formulations wherein “the osmotic pressure 296 were obtained” (Paragraph 45), “the osmotic pressure 320 were obtained” (Paragraph 53), the osmotic pressure 338 were obtained” (Paragraph 60), and so on.
As such, claim 11 is also rejected as prima facie obvious.
Claims 14-15 are drawn to a pharmaceutical composition (more specifically, as an ophthalmic formulation in the form of an eye drop (claim 15)) comprising an inclusion complex wherein a poorly soluble drug of Formula I (which embraces KR-67607) is entrapped within HPβCD in an aqueous solution of pH 10 or higher.
As discussed above, Choi et al teach an ophthalmic formulation in the form of an eye drop comprising KR-67607 (see, e.g., Page 3, Figure 1A and Page 3, Section 2.5 “[d]rugs were administered topically (one drop…) twice a day”), specifically disclosing “using KR-67607 in eye drops for long-term treatment to inhibit acute or continuous glaucoma development” (Page 10, Column 2).
However, Choi et al do not teach the compound as an inclusion complex, entrapped in 2-hydroxypropyl-β-cyclodextrin, in an aqueous solution of pH 10 or higher as claimed.
Yet, it is evident that KR-67607, which has a low logS and high cLogP (as demonstrated, for example, by ChemDraw (not currently available to the USPTO)) has low solubility in water.
And, as taught by Abelson et al, “[s]olubility enhancement is an important strategy when developing ophthalmic medications. Many drugs are poorly soluble in water, and substances must be added to increase solubility, raise the therapeutic concentration, and improve bioavailability”
Significantly, Bae et al teach that an “aqueous solution… for treating a dry eye syndrome” (Abstract) comprising the “poorly water-soluble drug” rebamipide (Paragraph 6) can be formulated by “dissolving rebamipide… cyclodextrin or a derivative thereof and a base into water to obtain a solution having pH of 8.5 or more” (Abstract, step (a)), more specifically, wherein the cyclodextrin is “2-hydroxypropyl-β-cyclodextrin” (Paragraph 14) and “the pH is 8.5 through… pH 10” (Paragraph 13), and then “adjusting the solution obtained… to pH of 7-8.5” (Abstract, step (b)), which exhibits improved bioavailability (Paragraph 37).
Accordingly, in further view of Abelson et al and Bae et al, it would have been prima facie obvious to formulate the KR-67607-containing eye drop of Choi et al as an inclusion complex comprising the KR-67607 entrapped in HPβCD in an aqueous solution of pH 10 or higher, wherein the pH of the eye drop is between 5 and 9. Recognizing that KR-67607 is poorly soluble in water, and further considering that “[s]olubility enhancement is an important strategy when developing ophthalmic medications” (as taught by Abelson et al), it would have been prima facie obvious to do so in order to increase solubility, raise the therapeutic concentration, and improve bioavailability of KR-67607 (based on Bae et al) with a reasonable expectation of success.
Carrying out step (a) to obtain a pharmaceutical composition renders claim 14 prima facie obvious whereas further carrying out step (b) to obtain an ophthalmic formulation in the form of an eye drop renders claim 15 prima facie obvious.
As such, claims 14-15 are also rejected as prima facie obvious.
Claims 16-17 are drawn to the composition/formulation of claim 15 which is “for the prevention or treatment of ischemic optic neuropathy” (claim 16), and/or “for the prevention or treatment of glaucoma” (claim 17)).
Applicant is advised that use limitations within product claims do not carry patentable weight unless the recitation of the intended use of the claimed invention results in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
As such, claims 16-17 are also rejected as prima facie obvious.
Claims 19-20 are drawn to the pharmaceutical composition/ophthalmic formulation of claims 14 and 15, respectively, wherein the poorly water-soluble drug protects the ocular tissue and/or optic nerve by a specified mechanism.
For the same reasons as discussed above regarding claims 2-3 and 18, claims 19-20 are also rejected as prima facie obvious.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CRAIG D RICCI whose telephone number is (571) 270-5864. The examiner can normally be reached on Monday through Thursday, and every other Friday, 7:30 am - 5:00 pm ET. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bethany Barham can be reached on (571) 272-6175. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CRAIG D RICCI/Primary Examiner, Art Unit 1611