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 .
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 6, 8-13, and 18-20 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Undue experimentation is a conclusion reached by weighing the noted factual considerations set forth below as seen in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). A conclusion of lack of enablement means that, based on the evidence regarding a fair evaluation of an appropriate combination 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.
These factors include:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on
the content of the disclosure.
The breadth of the claims - The nature of the invention
The claims are drawn to compositions comprising an orally bioavailable uridine prodrug and methods of using the same. The breadth of the claims includes all of the presently unknown potential prodrug derivatives embraced by claim.
The nature of the invention is clinical use of compounds and the pharmacokinetic behavior of substances in the human body.
The state of the prior art
Finding a prodrug is an empirical exercise. Predicting if a certain ester of a claimed alcohol, for example, is in fact a prodrug, that produces the active compound metabolically, in man, at a therapeutic concentration and at a useful rate is filled with experimental uncertainty. Although attempts have been made to predict drug metabolism de novo, this is still an experimental science. For a compound to be a prodrug, it must meet three tests. It must itself be biologically inactive. It must be metabolized to a second substance in a human at a rate and to an extent to produce that second substance at a physiologically meaningful concentration. Thirdly, that second substance must be biologically active. Determining whether a particular compound meets these three criteria in a clinical trial setting requires a large quantity of experimentation. Wolff (Medicinal Chemistry) summarizes the state of the prodrug art. (Wolff, Manfred E. "Burger's Medicinal Chemistry, 5ed, Part I", John Wiley & Sons, 1995, pages 975-977.) The table on the left side of page 976 outlines the research program to be undertaken to find a prodrug. The second paragraph in section 10 and the paragraph spanning pages 976-977 indicate the low expectation of success. In that paragraph the difficulties of extrapolating between species are further developed. Since, the prodrug concept is a pharmacokinetic issue, the lack of any standard pharmacokinetic protocol discussed in the last sentence of this paragraph is particularly relevant. Banker (Modern Pharmaceutics) (Banker, G.S. et al, "Modern Pharmaceutics, 3ed.", Marcel Dekker, New York, 1996, page 596) in the first sentence, third paragraph on page 596 states that “extensive development must be undertaken” to find a prodrug. Wolff (Medicinal Chemistry) in the last paragraph on page 975 describes the artisans making Applicants' prodrugs as a collaborative team of synthetic pharmaceutical chemists and metabolism experts.
The amount of direction provided by the inventor
The instant specification is not seen to provide adequate guidance which would allow the skilled artisan to extrapolate from the disclosure and examples provided to make or use the claimed compounds commensurate in the scope with the instant claims. There is a lack of data and examples which adequately represent the claims as written. The examiner notes, there has not been provided sufficient instruction or sufficient methodological procedures to support the scope of the prodrug compounds instantly claimed.
The existence of working examples
There are no working examples showing how to determine if a compound would be a prodrug of uridine. Applicants have shown uridine triacetate is a prodrug of uridine and note that ester prodrugs of uridine have been found to improve its bioavailability, only 2’,3’,5’-tri-O-acetyluridine (uridine triacetate) has been found adequate to deliver sufficient uridine for some clinical purposes – see page 1, lines 14-19 of the present specification.
The quantity of experimentation needed to make and use the invention based on the content of the disclosure
It is well established that “the scope of enablement varies inversely with the degree of unpredictability of the factors involved", and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). Thus, undue experimentation will be required to determine if any particular compound of claim 1 is, in fact, a prodrug. Since the structures of these “prodrugs” are uncertain, direction for their preparation must also be unclear. Directions to a team of synthetic pharmaceutical chemists and metabolism experts of how to search for a "prodrug" hardly constitute instructions to the BS process chemist of how to make such a compound.
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.
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.
Claim(s) 6-13 and 16-20 are rejected under 35 U.S.C. 103 as being unpatentable over US 7,709,459 (‘459) in view of WO2013/012760 (‘760).
The claims of the present application are drawn to compositions comprising therapeutically effective amount so of an orally bioavailable uridine prodrug and a ketoleucine compound. Dependent claims provide the uridine prodrug is uridine triacetate and that the ketoleucine compound I optionally ketoleucine. Also claimed are methods of treating muscle wasting diseases such as cachexia in mammals, and humans.
‘459 is drawn to compositions and methods of treating muscle wasting disease such as cachexia in humans comprising administering triacetyluridine (also named uridine triacetate as in the present claims) - see claim 1. What is not taught is to add a ketoleucine to the composition.
However, ‘760 teaches that compositions comprising keto-isocaproic acid (KIC/ketoleucine – see [0006]) are effective in treating a subject having cachexia or muscle wasting (see [00370].
It would have been obvious to one of ordinary skill in the art to combine the two compositions comprising triacetyluridine and ketoleucine and form a new composition and use them in the same manner as they are taught to be used individually – treating cachexia. Regarding the additional agents used in the art, these additional agents are not delimited from being included in the present compositions and methods as the present claims use open “comprising” claim language. It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose. The idea of combining them flows logically from their having been individually taught in the prior art. In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); and Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious). In the instant case, ‘459 teaches to use triacetyluridine to treat cachexia and muscle wasting. ‘760 teaches to use ketoleucine to treat cachexia and muscle wasting. Thus it would have been obvious to one of ordinary skill in the art at the time of the invention to combine the art recognized agents, specifically ketoleucine and triacetyluridine, to form a new composition which will be used for the very same purpose, an agent to treat cachexia and muscle wasting, with these references before them. One would have been motivated to combine these agents to form a new composition which would be used for the very same purpose. Likewise, applicants have shown nothing surprising about the combination of triacetyluridine and ketoleucine to overcome this rejection. Further, it would be obvious to practice these methods on humans as the references are drawn to treating humans.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 6-13 and 16-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 of U.S. Patent No. 7,709,459 in view of WO2013/012760 (‘760).
The claims of the present application are drawn to compositions comprising therapeutically effective amount so of an orally bioavailable uridine prodrug and a ketoleucine compound. Dependent claims provide the uridine prodrug is uridine triacetate and that the ketoleucine compound I optionally ketoleucine. Also claimed are methods of treating muscle wasting diseases such as cachexia in mammals, and humans.
‘459 is drawn to methods of treating cachexia comprising administering triacetyluridine (also named uridine triacetate as in the present claims) - see claim 1. What is not taught is to add a ketoleucine to the composition.
However, ‘760 teaches that compositions comprising keto-isocaproic acid (KIC/ketoleucine – see [0006]) are effective in treating a subject having cachexia or muscle wasting (see [00370].
It would have been obvious to one of ordinary skill in the art to combine the two compositions comprising triacetyluridine and ketoleucine and form a new composition and use them in the same manner as they are taught to be used individually – treating cachexia. Regarding the additional agents used in the art, these additional agents are not delimited from being included in the present compositions and methods as the present claims use open “comprising” claim language. It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose. The idea of combining them flows logically from their having been individually taught in the prior art. In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); and Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious). In the instant case, ‘459 teaches to use triacetyluridine to treat cachexia. ‘760 teaches to use ketoleucine to treat cachexia and muscle wasting. Thus it would have been obvious to one of ordinary skill in the art at the time of the invention to combine the art recognized agents, specifically ketoleucine and triacetyluridine, to form a new composition which will be used for the very same purpose, an agent to treat cachexia and muscle wasting, with these references before them. One would have been motivated to combine these agents to form a new composition which would be used for the very same purpose. Likewise, applicants have shown nothing surprising about the combination of triacetyluridine and ketoleucine to overcome this rejection. Further, it would be obvious to practice these methods on humans as the references are drawn to treating humans.
Allowable Subject Matter
Claims 1-5 and 14-15 are allowed.
The closest prior art is seen to be US 7,709,459 which is drawn to the compound uridine triacetate and the use in treating cachexia. However, the art is silent as to the present compound which is drawn to 5’-O-ketoleucyl-2’,3’-di-O-acetyluridine. ‘459 does contemplate various amino acids attached to their compounds – see column 10, lines 42-64, however the compounds therein would not have comprised the ketoleucyl moiety CH3CH(CH3)C(O)C(O)- attached to the C5’ carbon atom of the ribose moiety through the oxygen bridge. Thus one would have to choose leucine at the 5’-position, and acetyl at the 2’ and 3’-positions and also modify the leucine with an additional keto group to arrive at the present compounds, which would not be seen as being an obvious pathway.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TRAVISS C MCINTOSH III whose telephone number is (571)272-0657. The examiner can normally be reached Monday-Friday 9AM-5:30PM EST.
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TRAVISS C. MCINTOSH III
Primary Examiner
Art Unit 1693
/TRAVISS C MCINTOSH III/Primary Examiner, Art Unit 1693