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 .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Current Status of 18/881,324
This Office Action is responsive to the amended claims of 6 January 2025.
Claims 1-17 and 19-20 have been examined on the merits. Claims 2-17 are currently amended. Claims 1 and 19-20 are original.
Priority
The effective filing date is 7 July 2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 6 January 2025, is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-17 and 19-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Factors to be considered in making the determination as to whether one skilled in the art would recognize that the applicant was in possession of the claimed invention as a whole at the time of filing include: (a) Actual reduction to practice; (b) Disclosure of drawings or structural chemical formulas; (c) Sufficient relevant identifying characteristics such as: (i) Complete structure, (ii) Partial structure, (iii) Physical and/or chemical properties or (iv) Functional characteristics when coupled with a known or disclosed correlation between function and structure; (d) Method of making the claimed invention; (e) Level of skill and knowledge in the art and (f) Predictability in the art. While all of these factors are considered, a sufficient number for a prima facie case are discussed below.
Independent claims 1 and 19-20 contain “prodrug”. Here, Applicant provides no guidance as to ‘prodrugs'. The artisan understands that prodrug forms are generally determined a posteriori, and it is only through trial and error that prodrugs are identified. The artisan understands the concept of prodrugs, however the artisan does not per se understand what specifically describes a specific prodrug form. The reference HAN (Han, H. “Targeted Prodrug Design to Optimize Drug Delivery.” AAPS Pharmsci. (2000), Vol. 2 (1) article 6, pp. 1-11), acknowledges there is no specific definition for prodrug (e.g. page 1), but that in general, the 'prodrug' is an inactivated form of the drug that activates in vivo to the active form. While some prodrugs are simply esters or salts, other prodrug forms are not chemically or structurally related to their active form, one example being glucose as the prodrug form of hydrogen peroxide (Table 1, page 5), as is hypoxanthine, thus posing a problem as to understanding what is the exact prodrug form of a compound, as hydrogen peroxide has two prodrug forms in the limited set of compounds exemplified in Han.
According to the reference ETTMAYER (Ettmayer, P., et al. “Lessons Learned from Marketed and Investigational Prodrugs.” J. Med. Chem. (2004) 47(10), pages 2393-2404), prodrugs are often accidental discoveries. Furthermore, the reference TESTA (Testa, B. “Prodrug research: futile or fertile?” Biochem. Pharm. (2004) 68, pages 2097-2106), teaches that, “A number of challenges await medicinal chemists and biochemists carrying out prodrug research, such as the additional work involved in synthesis, physicochemical profiling, pharmacokinetic profiling and toxicological assessment. Two of these challenges are introduced here, namely biological variability and toxicity potential. The challenge of biological variety results principally but not only from the huge number and evolutionary diversity of enzymes involved in xenobiotic metabolism. Inter- and intra-species differences in the nature of these enzymes, as well as many other differences such as the nature and level of transporters, may render prodrug optimization difficult to predict and achieve.” (Testa, page 2098).
Methods of making compounds, in general, are known to the artisan, however the methods of making any specific prodrug are complex and poorly understood, requiring an undue amount of experimentation to determine if a compound is actually a prodrug, and the instant specification fails to provide guidance to overcome the complexity and difficulties known to the artisan, as discussed above.
Therefore, claims 1 and 19-20 are rejected under 35 USC 112(a) as lacking written description possession to all of the “prodrug” forms thereof, as currently claimed. Moreover, claims 2-17 are similarly rejected as lacking written description under 35 USC 112(a) since these claims refer back to claim 1 but do not remedy the rationale underpinning the basis for rejecting claim 1.
This rejection can be rendered moot by deleting all occurrences of “prodrug” from all of the claims.
The description requirement of the patent statue requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736, F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate.”) Accordingly, it is deemed that the specification fails to provide adequate written description for the genus of the claims and does not reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the entire scope of the claimed invention.
Claims 1-17 and 19-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description possession rejection.
Applicants do not show evidence of actual possession of a representative number of species of “substituted derivatives thereof” or “metabolites thereof” (of fasudil) as per instant claims 1 and 19-20.
While Applicants’ Specification does show that Applicants were in actual possession of fasudil-comprising liposomes (see, Examples 1-22 starting on page 44 of the Specification), the Examiner cannot find evidence that Applicants were in actual possession of any “substituted derivatives thereof” or “metabolites thereof” of fasudil. Every word in the claim carries meaning. Please see MPEP 2164.
Therefore, the “substituted derivatives thereof” or “metabolites thereof” of independent claims 1 and 19-20 cause claims 1 and 19-20 to be rejected under 35 USC 112(a) as lacking written description.
Moreover, claims 2-17 are similarly rejected as lacking written description under 35 USC 112(a) since these claims refer back to claim 1 but do not remedy the rationale underpinning the basis for rejecting claim 1.
To render moot this rejection: please delete all occurrences of “substituted derivatives thereof” AND “metabolites thereof” from all of the claims.
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.
Claims 1-8 and 19 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by:
GUPTA (Gupta, V., et al. “Liposomal Fasudil, a Rho-Kinase Inhibitor, for Prolonged Pulmonary Preferential Vasodilation in Pulmonary Arterial Hypertension.” J. of Controlled Release. 28 April 2013, Epub 23 January 2013, Vol. 167, No. 2, pp. 1-25).
The prior art reference GUPTA teaches an oral aqueous pharmaceutical composition comprising a liposome, the liposome comprising fasudil (fasudil encapsulated in aerosolized liposomes that may be delivered via nebulization, which involves oral inhalation (oral pharmaceutical composition)-page 2, 3d para; page 9, 3d para; and table 2)). This anticipates instant claims 1 and 7-8.
GUPTA teaches the oral pharmaceutical composition of instant claim 1, per, above, and further teaches that the liposome comprises a phospholipid and cholesterol (liposomes were prepared using DPPC (phospholipid/phosphatidylcholine) and cholesterol-see page 3, 1st and 2d paragraphs). This anticipates instant claims 2 and 5-6. DPPC consists of two palmitic acid groups phospholipid attached to phosphatidylcholine head group, which anticipates instant claims 4-5.
GUPTA teaches the oral composition of the preceding claims, and GUPTA further discloses wherein an esterified fatty acid of the phospholipid comprises a saturated fatty acid, or an unsaturated fatty acid, or both (liposomes were prepared using DPPC, which comprises saturated esterified fatty acids-see page 3, 1st and 2d paragraphs). This anticipates instant claim 3.
The GUPTA reference teaches a method for preparing fasudil encapsulated in aerosolized liposomes that may be delivered via nebulization, which involves oral inhalation (oral administration) (page 2, 3d para; page 3, 1st and 2d para; page 9, 3d para; and table 2). The method comprises: mixing a diacylglyceride, cholesterol, a rho kinase inhibitor, and optionally, a cellulose ether in a volatile organic solvent to produce a first composition, the rho kinase inhibitor comprising fasudil; subjecting the first mixture to evaporation to produce a second composition; applying an aqueous solution to the second composition to form a third composition; and imparting energy to the third composition to produce a fourth composition, the fourth composition comprising the fasudil-comprising liposomes formulated for oral administration (liposomes were prepared using diacylglycerol DPPC and cholesterol, wherein the lipids were dissolved in a 4:1 mixture of chloroform and methanol (volatile organic solvent) and dried overnight at 40*C to form a thin film in a round bottom flask using a rotatory evaporator (subjecting the first mixture to evaporation to produce a second composition), following which fasudil was incorporated by rehydrating the dried film with fasudil in PBS (mixing rho kinase inhibitor comprising fasudil, and applying an aqueous solution to the second composition to form a third composition) and the rehydrated film was sonicated for 1 h at 25*C (imparting energy to the third composition to produce a fourth composition), and finally fasudil-encapsulating liposomes were extruded and formulated for nebulization (fourth composition comprising the fasudil-comprising liposomes formulated for oral administration-page 2, 3d para; page 3, 1st and 2d para; page 9, 3d para; and table 2). This anticipates instant claim 19.
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 1-17 and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over:
GUPTA (Gupta, V., et al. “Liposomal Fasudil, a Rho-Kinase Inhibitor, for Prolonged Pulmonary Preferential Vasodilation in Pulmonary Arterial Hypertension.” J. of Controlled Release. 28 April 2013, Epub 23 January 2013, Vol. 167, No. 2, pp. 1-25),
in view of:
ORADEL (WO 2006/062544 A1, provided by Applicants and referenced in IDS of 6 January 2025),
in view of:
YAN (Yan, Yuqing, et al. “Therapeutic potentials of the Rho kinase inhibitor fasudil in experimental autoimmune encephalomyelitis and the related mechanisms.” Metabolic Brain Disease. (2019), 34: 377-384),
and in further view of:
ANSEL (Ansel, Howard C., et al. “Pharmaceutical Dosage Forms and Drug Delivery Systems.” 7th ed. (1999)).
Determining the scope and contents of the prior art:
The prior art reference GUPTA teaches instant claims 1-8 and 19, see, above.
The prior art reference ORADEL teaches coating drug-comprising liposomes to form drug-comprising enteric coated liposomes (liposomes prepared for oral administration in the form of drug-comprising enteric-coated proliposome tablets-page 40, lines 10-24).
The prior art reference ORADEL teaches cellulose ether or polymethacrylate coatings (see ORADEL claim 5). This teaches instant claim 11.
The prior art reference YAN teaches that fasudil is useful to treat the following neurodegenerative diseases: the wandering associated with the memory loss of Alzheimer’s disease (page 382), ALS (page 378), Parkinsons disease (page 378), and multiple sclerosis (page 378), thereby teaching instant claims 13-17.
The prior art reference ANSEL teaches that physicians routinely change the dosing and dosing regimen of medicaments for patients (a “routinely optimized results-oriented variable”) based on many factors, such as body mass index (page 48).
Ascertaining the differences between the prior art and the claims at issue:
While GUPTA teaches instant claims 1-8 and 19, above, it does not teach enteric coated liposomes or coating the fasudil-comprising liposomes to form the fasudil-comprising enteric coated liposomes.
While ORADEL teaches coating drug-comprising liposomes to form drug-comprising enteric coated liposomes (liposomes prepared for oral administration in the form of drug-comprising enteric-coated proliposome tablets-page 40, lines 10-24), it does not teach fasudil-comprising enteric coated liposomes.
While YAN teaches that fasudil is useful to treat the following neurodegenerative diseases: the wandering associated with the memory loss of Alzheimer’s disease (page 382), ALS (page 378), Parkinsons disease (page 378), and multiple sclerosis (page 378), it does not teach the enteric-coasted fasudil-comprising liposomes of some of the instant claims.
While ANSEL teaches that physicians routinely change the dosing and dosing regimen of medicaments for patients (a “routinely optimized results-oriented variable”) based on many factors, such as body mass index (page 48), the ANSEL reference does not teach all of the limitations of any of the independent claims 1 and 19-20.
Resolving the level of ordinary skill in the pertinent art:
The artisan is knowledgeable in formulating enteric coated liposomes for any active pharmaceutical ingredient. The artisan also knows how to routinely optimize doses, concentrations, and dosing regimens of active pharmaceutical ingredients (e.g., fasudil) to optimize therapeutic efficacy.
Considering objective evidence present in the application indicating obviousness or nonobviousness:
The instant claims are prima facie obvious in light of the combination of references GUPTA in view of: ORADEL, YAN, and ANSEL.
The artisan would be expected to modify the fasudil-comprising liposomes as taught by GUPTA with enteric coatings (taught by ORADEL) thereby arriving at enteric-coated fasudil-comprising liposomes that are orally delivered, in order to slow degradation of the liposome contents (fasudil API) in the stomach and increase bioavailability.
The artisan would be motivated to modify the fasudil-comprising liposomes as taught by GUPTA with enteric coatings (taught by ORADEL) thereby arriving at enteric-coated fasudil-comprising liposomes that are orally delivered, in order to slow degradation of the liposome contents (fasudil API) in the stomach and increase bioavailability. The motivation would be to slow stomach degradation, increase bioavailability, and provide an improved fasudil-comprising liposomal formulation. This therefore teaches instant claims 10 and 20.
Moreover, the artisan would be expected and motivated to design the liposome to mask the taste of the bitter taste of the fasudil. This teaches instant claim 9.
Claim 12 is drawn to concentrations of fasudil. The concentrations of claim 12 are interpreted as results-oriented variables the artisan would be expected to routinely optimize to maximize therapeutic efficacy of the invention. In fact, the prior art reference ANSEL teaches that physicians routinely optimize dosages of active pharmaceutical ingredients (based on patient body mass index, etc.) to maximize therapeutic efficacy (see page 48). Moreover, the Specification and claims are silent as to how/if these concentrations are critical.
Generally, differences in concentration or temperature (results-oriented variables) will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here 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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 809, 10 USPQ2d 1843, 1848 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989)(Claimed ratios were obvious as being reached by routine procedures and producing predictable results); In re Kulling, 897 F.2d 1147, 1149, 14 USPQ2d 1056, 1058 (Fed. Cir. 1990)(Claimed amount of wash solution was found to be unpatentable as a matter of routine optimization in the pertinent art, further supported by the prior art disclosure of the need to avoid undue amounts of wash solution); and In re Geisler, 116 F.3d 1465, 1470, 43 USPQ2d 1362, 1366 (Fed. Cir. 1997)(Claims were unpatentable because appellants failed to submit evidence of criticality to demonstrate that that the wear resistance of the protective layer in the claimed thickness range of 50-100 Angstroms was "unexpectedly good"); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree "will not sustain a patent"); In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416, 82 USPQ2d 1385, 1395 (2007) (identifying "the need for caution in granting a patent based on the combination of elements found in the prior art."). See MPEP 2144.05(II)(A). This teaches instant claim 12.
Applicants are encouraged to provide evidence of secondary considerations, such as surprising/unexpected results, in order to render moot the obviousness rejection and expedite allowance.
Conclusion
No claims are presently allowable as written.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOHN S KENYON whose telephone number is (571)270-1567. The examiner can normally be reached Monday-Friday 10a-6p.
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/JOHN S KENYON/Primary Patent Examiner, Art Unit 1625
