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 .
Claims 1-35 are pending in the application. Claims 36-41 have been canceled. Preliminary amendment filed 18 August 2023.
Priority
This application is a 371 of PCT/US2022/017134 filed 02/21/2022, which claims the benefit of 63152356 filed 02/23/2021. The parent application 63152356 to which priority is claimed is seen to provide adequate support under 35 U.S.C. 112 for claims 1-35 of this application.
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 33 and 35 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating HIV using the compounds of claim 1 and claim 31, and pharmaceutically acceptable salts thereof, does not reasonably provide enablement for a method of preventing infection in a patient using the compounds. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
A conclusion of lack of enablement means that, based on the evidence regarding each of the factors below, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation.
(A) The breadth of the claims
(B) The level of one of ordinary skill
(C) The amount of direction provided by the inventor
(D) The existence of working examples
(E) The level of predictability in the art
(F) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Nature of the Invention
Claims 33 and 35are drawn to a method preventing HIV infection in a patient via administration of the compound as in claim 1or claim 31.
The breadth of the claims
The pharmaceutical art is unpredictable, requiring each embodiment to be individually assessed for physiological activity. In re Fisher, 166 USPQ 18 indicates that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute.
The instant claims recite the term ‘preventing’. The term prevention or preventing is defined in the specification as follows (page 7, lines 9-12):
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The term prevention according to the definition provided encompasses absolute prevention of HIV infection. In the instant case prevention according to the definition provided means keeping the said HIV infection from happening in a mammal and is interpreted to mean the complete and total blocking of the infection for an indefinite period of time. Prevention is seen to include the administration of the claimed compound to a healthy mammal, and subsequent exposure to conditions that would cause the infection, wherein the claimed compound prevents said exposure to the infection from manifesting itself in said mammal so exposed. Any therapy which merely reduces the severity of the infection, or which is effective for a period shorter than the subject’s remaining lifespan, is considered to be ineffective at preventing. In general, prevention is not possible as any so-called preventive effects of a drug therapy are expected to cease when the drug is cleared from the patient’s system. More generally, prevention of the claimed infection in the sense being used herein is not a recognized clinical outcome in the art, as no treatment is perfectly effective. Therefore, one of ordinary skill in the art would consider it highly unlikely that the instant compounds will prevent HIV infection.
The amount of direction provided by the inventor
The specification (Background of the Invention) teaches that HIV continues to rise, and that long-term suppression of viral replication with antiretroviral drugs is the only option for treating HIV infection. Drugs have been approved for patient survival and quality of life. This means that prevention is not possible since HIV infections continue to rise.
The existence of working examples
The working examples set forth in the instant specification are drawn to synthesis of compounds of instant formula I. There are no examples in vivo or in vitro, to show that the instant compounds can prevent HIV infection.
The level of Predictability in the Art
It is noted that the pharmaceutical art is unpredictable, requiring each embodiment to be individually assessed for physiological activity. In re Fisher, 427.2d 833, 166 USPQ (CCPA 1970) indicates that the more unpredictable an area is, the more specific enablement is necessary to satisfy the statute.
As disclosed in The Merck Manual (1992, pages 2190-2196) HIV infections are transmitted via different modes (see under Etiology and Epidemiology). The approach is to prove medical supportive are via aggressive treatment of infections as they occur. No vaccine against HIV infection is available nor is one likely to be available for years (page 2194, last para to page 2195 first para; page 2196, first para under sub-title: Public Health Issues).
According to Galarraga et al (BMC Public Health, 2009, 9(Suppl I), 1-14), more than 25 years into the AIDS epidemic and billions of dollars of spending later, there is still much work to be done both on costs and effectiveness to adequately inform HIV prevention planning (Abstract; page 11, right col. last para).
Therefore, there is unpredictability in the art regarding methods of preventing infections using a single drug as recognized by skilled artisans in the field.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure
In view of the information set forth, the instant disclosure is not seen to be sufficient to enable prevention of HIV infections using the compounds of claim1 and the combination as in claim 31.
Genentech, 108 F.3d at 1366, states that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion” and “patent protection is granted in return for an enabling disclosure of an invention, not for ideas that may or may not be workable”.
Therefore, in view of the Wands factor and In re Fisher (CCPA 1970) discussed above, to practice the claimed invention herein, a person of skill in the art would have to engage in undue experimentation with no assurance of success.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (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.
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.
Claim(s) 1-32 and 34 are rejected under 35 U.S.C. 103 as being unpatentable over Rosa et al (WO 2020/178767 A1; cited in IDS filed 08/18/2023) in view of Kohgo et al (EP 1589026 A1; cited in IDS filed 08/18/2023) and further in view of Huang et al (WO 2013/187978 A1; cited in IDS filed 08/19/2023).
According to Rosa, its compound of formula (I):
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X is F, R5=R6 = H. It has the ethynyl moiety at the 4’ position. It is an ester at the 5’ position since R2 can be alkyl. R3 at the 3’ position can be –(C=O)-(C1-C24)alkyl, which would be an ester (limitation of claim 17). The compound of instant formula (I) also has an ester at the same position if X is a bond. Rosa discloses examples in Table 1, starting at page 24, compound # 15, and various types of ester substitutions at the 3’-position including a carbonate (compound # 43) which is in the definition of X in formula (I) in claim 1, and also in compound # 48 in Table 1 in instant claim 26. The compound of Rosa including pharmaceutically acceptable salts are useful for treating HIV infection (page 3, line 11 through page 4, line 29; page 12, line 34 through page 14, line 7; Table 1 at page 22; part of the limitations of claims 1, 27, 32 and 34). The compounds can be used in combination with one or more agents useful for treatment of HIV (page 34, line 17 through page 36, line 7; part of the limitation of claim 31). Pharmaceutical compositions include parenteral injection form and oral composition (page 37, lines 8 through 29; part of the limitations of claims 28-30)
Rosa et al does not teach the substitutions on the phosphorus at the 5’ position as in instant formula (I) in claim 1, and does not teach some of the limitations of claims 2-16 and 18-26.
Kohgo et al teaches compound of formula (I) wherein X can be F, R1 is ethynyl and R2 can be H or phosphate residue or phosphate derivative residue including salts (para 0011, lines 2-18; para 0019; part of the limitations of claim 1).
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The invention also includes pharmaceutical compositions (para 0012; part of the limitation of claim 27). The compound is used in a method of treating HIV infection (para 0094; method as in claims 32 and 34).
From the teachings of Rosa and Kohgo one of ordinary skill in the art will recognize that the compound of Rosa is a prodrug of the compound of Kohgo. According to the teachings of Rosa, compounds that have substitutions at the 3’ and 5’ positions as in the instant case are useful as active agents for the treatment of HIV infection.
Huang et al teaches purine derivatives to form prodrugs. Examples of such prodrugs are the second and third compound on the right column in the Table at page 55. The second compound when substituted with a fluorine on the purine ring would have the same substitutions on the 5’ position and the purine ring, except the 3’ position. In addition, Hung teaches various substitutions on the phosphorus at the 5’-position which reads on R1 in instant formula (I) in claims 1-5, and 9. Huang teaches alkylene-aryl for R1 and the -NH-C(R1R2)-C(O)O-R4 substitutions that are attached to the phosphorus wherein R4 is alkyl and aryl. R4 in Huang corresponds to R3 in instant formula (I) in claim 1 (page 13, lines 1-8 for R2 and R3 and pages 17-18).
Huang’s compounds are for treating viral infections too. Even though it does not expressly teach the use of its compounds for treating HIV infection, one of ordinary skill in the art will recognize that the prodrug moiety at the 5’ position is a suitable moiety for substitution at the 5’ position for making 5’ prodrugs of the compound of Kohgo which is used for treating HIV infection. Huang teaches compositions of its compounds like tablets and also numerous other formulations that can be made (page 41, lines 10-23, and page 42, lines 18-22; limitation of claim 30).
Rosa teaches R3O substitution at the 3’ position of the deoxyribose ring which can be –(C=O)-O-(C1-C24) alkyl. This reads on the ester groups at the same position on the deoxyribose in compounds 1-106, and 108-128 in claim 26.
Huang teaches compounds wherein the phosphorus has the aminoalkyl ester groups as a substitution. This substitution is also seen in compounds 1-106, and 108-128 in claim 26. R2 and R3 in Huang’s compounds can be a substituted alkyl and H (page 13, lines 1-2). If one of them, for e.g. R2 is H then the other can be a substituted alkyl. Since a substitution can also be aryl for either R2 or R3, it would be obvious to use a -CH2-phenyl, which is a substituted alkyl, as a substitution on the carbon to the left of the nitrogen as in compounds 1-107 in claim 26. In the compounds in claim 26, a phenoxy group appears as a substitution on the phosphorus. Huang, at page 14, teaches a methyl substituted benzyloxy group at this same position. In view of this teaching one of ordinary skill in the art will find it obvious to use a phenoxy substitution on the phosphorus as a variant. Since most of the substitutions on the phosphorus and the 3’-position of the deoxyribose as in the compounds of claim 26 are taught, one of ordinary skill in the art will find it obvious to make all the compounds in claim 26 as variants for use in the method of treating HIV infections.
MPEP 2141 states, "The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit. The Court quoting In re Kahn, 441 F.3d 977, 988, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006), stated that "[R]ejections on obviousness cannot be sustained by mere conclusatory statements; instead, there must be some articulated reasoning with some rational underpinning to support the legal conclusion of obviousness.'" KSR, 550 U.S. at, 82 USPQ2d at 1396. Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) " Obvious to try " choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention."
According to the rationale discussed in KSR above, the rationale in (G) above is seen to be applicable here since based on the prior art teachings, one of ordinary skill in the art can arrive at the claimed compounds as alternatives and use them in a method of treating HIV infection in a patient.
Thus, the claimed invention as a whole would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention over the combined teachings of the prior art. Huang teaches that when Rb on the phosphorus in formula F1 is a phenyl and Ra is an amino acid, Rb would be simultaneously released. Moreover, phosphoramidite prodrugs with Rb as benzyl group with substitution on the phenyl ring did not demonstrate biological usefulness sine these groups in phosphoramidite prodrugs of nucleoside are too stable to be cleaved to produce the active nucleoside (page 3, lines 7-22). This provides motivation for the artisan to substitute the substituted benzyloxy group in the compound of Huang with a phenoxy group on the phosphorus as in the compounds of claim 26. One of ordinary skill in the art would look for other compounds that are useful as alternative for the treatment of HIV infection in a patient. The artisan can make all the substitutions as in claims 1-26 in view of the teachings of the prior art in order to look for compounds that have enhanced antiretroviral activity. Such is well within the skill level of the artisan to recognize and perform based on the teachings of the prior art substitutions and methods for making them.
Conclusion
Pending claims 1-35 are rejected
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/GANAPATHY KRISHNAN/ Primary Examiner, Art Unit 1693