DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Status of the Claims
Claims 1-12 are pending in the instant application and subject to examination herein.
Claim Objections
Claim 11 is objected to because of the following informalities: the disease “prostatitis” is unnecessarily listed twice in the provided Markush group of diseases, and is misspelled as “prostatitits” in one instance. Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
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 10 and 12 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 for treating a disease mediated by a P2X3 or P2X2/3 receptor antagonist wherein the disease is urinary tract disease, does not reasonably provide enablement for method for treating all other diseases mediated by a P2X3 or P2X2/3 receptor antagonist. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)” (emphasis added). The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed more recently in Liebel-Flarsheim Co. v. Medrad, Inc., 481 F.3d 1371, 82 USPQ2d 1113; Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008).
In evaluating the enablement question, several factors are to be considered. Note In re Wands, 8 USPQ2d 1400 and Ex parte Forman, 230 USPQ 546. These factors include: 1) The nature of the invention, 2) the state of the prior art, 3) the amount of direction or guidance present, 5) the presence or absence of working examples, 6) the breadth of the claims, and 7) the quantity of experimentation needed. The determination that “undue experimentation” would have been needed to make and use the claimed invention is not a single, simple factual determination. Rather, it is a conclusion reached by weighing all the above noted factual considerations.
The Nature of the Invention and Breadth of the Claims
The instant claims recite ‘a method for treating a disease mediated by a P2X3 or P2X2/3 receptor antagonist’. The instant claims thereby cover ‘diseases’ that are known to exist and those that may be discovered in the future. The use disclosed in the specification is as pharmaceutical therapeutic agents as P2X3 receptor antagonist, a P2X2/3 receptor antagonist, or both, useful to treat a wide list of diseases, some of which are listed in page 34 and page 98.
The State of the Prior Art
The state of the art shows that a potent and selective antagonist of P2X3 and P2X2/3 receptors effectively reduces both nerve injury and chronic inflammatory nociception, but P2X3 and P2X2/3 receptor activation may not be a major mediator of acute, acute inflammatory, or visceral pain – see for example, Jarvis (Jarvis, M. F., et al.; Proceedings of the National Academy of Science, v99, pp17179-17184; 2002). Jarvis teaches a study of A-317491, a potent and selective non-nucleotide antagonist of P2X3 and P2X2/3 receptors (Abstract). Jarvis teaches that A-317491 potently blocks recombinant human and rat P2X3 and P2X2/3 receptor-mediated calcium flux (Ki = 22-92 nM) and was highly selective (IC50 >10 mM) over other P2 receptors and other neurotransmitter receptors, ion channels, and enzymes. A-317491 also blocked native P2X3 and P2X2/3 receptors in rat dorsal root ne ganglion neurons. Blockade of P2X3 containing channels was stereospecific because the R-enantiomer (A-317344) of A-317491 was significantly less active at P2X3 and P2X2/3 receptors. A-317491 dose-dependently (ED50 = 30 mmol/kg s.c.) reduced complete Freund's adjuvant-induced thermal hyperalgesia in the rat. A-317491 was most on potent (ED50 = 10-15 mmol/kg s.c.) in attenuating both thermal hyperalgesia and mechanical allodynia after chronic nerve constriction injury. The R-enantiomer, A-317344, was inactive in these chronic pain models. Although active in chronic pain models, A-317491 was ineffective (ED50 > 100 mmol/kg s.c.) in reducing nociception in animal models of acute pain, postoperative pain, and visceral pain.
The Amount of Direction or Guidance Present
The scope of the claims is not adequately enabled solely based on the activity related to P2X3 receptor provided in the specification. Pharmacological data provided in Example 70 is drawn to a test the P2X3 or P2X2/3 receptor activity (paragraphs [0508]-[0512], including Table 3), however, there is nothing in the disclosure regarding how this in vitro data correlates to the treatment of all the diverse disorders embraced by the instant claims. Further, none of the compounds assayed in Example 70 are in scope of instant formula (I) as claimed in claim 10, and there is no reasonable basis for assuming that the myriad of compounds embraced by the claims will all share the same physiological properties since they are so structurally dissimilar as to be chemically non-equivalent and there is no basis in the prior art for assuming the same. Thus, the scope of the claims is not adequately enabled solely based on the activity related to P2X3 receptor provided in the specification. Applicants have not provided any competent evidence or disclosed tests that are highly predictive for the pharmaceutical use of the instant compounds. Pharmacological activity in general is a very unpredictable area. Note that in cases involving physiological activity such as the instant case, “the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved”. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
The Quantity of Experimentation Needed
In view of the breadth of the claim, the chemical nature of the invention, the unpredictability of ligand-receptor interactions in general, and the lack of working examples regarding the activity of the claimed compounds, one having ordinary skill in the art would have to undergo an undue amount of experimentation to use the invention commensurate in scope with 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.
(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.
Claim 10 is rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Hitchings (U.S. Patent No. 2,657,206).
Claim 10 is drawn to a method for treating a disease mediated by a P2X3 or P2X2/3 receptor antagonist, comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein instant formula (I) represents of genus of phenyloxy-aminopyrimidine compounds bearing additional substituents R1-R8 and Y, and optional substituent D, as shown in the table below. Hitchings discloses pyrimidine derivatives having valuable antibacterial properties (Abstract), including multiple compounds in scope of instant formula (I), for example Hitchings’ Example 531, shown in the table below (Col. 8, lines 54-66):
Claim Number(s) of Instant Application
Instant Application
Hitchings
10
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164
266
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wherein:
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264
522
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Hitchings discloses that the compounds disclosed therein have antibacterial activity by virtue as inhibitors of microbial utilization of pteroylglutamic (folic) acid (Col. 1, lines 15-29). As per the instant Specification, diseases associated with pain mediated by a P2X3 receptor or P2X2/3 receptor include “parasitic or bacterial infection” (paragraphs [0216] and [0241]).
Thus, claim 10 is anticipated by the disclosure of Hitchings.
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 1-12 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 8 and 18 of U.S. Patent No. 7,858,632 B2 (hereafter referred to as “Broka”). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of Broka anticipate the instant claims. Broka claims a genus of aryloxy-pyrimidine-2,4-diamine compounds, designated as “formula (II)” that fully and closely overlaps with the instant genus, as shown below:
Claim Number(s) of Instant Application
Instant Application
Broka
1
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164
266
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160
268
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wherein:
Broka’s formula II includes the limitation of wherein “R3 and R4 together with the atoms to which they are attached may form a five or six-membered ring that optionally includes one or two heteroatoms selected from O, S and N” among multiple options for the positions R3 and R4, and claim 18 specifically claims a compound2 that anticipates this limitation, as shown in the table below:
Claim Number(s) of Instant Application
Instant Application
Broka (claim 18)
1
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164
266
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wherein:
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322
294
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Instant claims 2, 3 and 6-8 further limit instant claim 1, each to a narrower genus that continues to overlap with Broka’s claim 1 and is anticipated by the compound shown above from Broka’s claim 18.
Instant claims 4-5 further narrow instant claim 1 in precisely the same manner that Broka’s claim 1 is further limited by Broka’s claims 2 and 3, respectively.
Instant claim 9 further limits instant claim 1 to wherein the extra-annulation formed by combination of R3 and R4 is precisely a 5-membered ring and must form a pyrrole or pyrazole ring. This limitation is within scope of Broka’s formula II, and while Broka does not specifically further limit formula (II) to this scope nor claim by name a compound that anticipates this structural limitation, a person of ordinary skill in the art would have been motivated to select any of the species or a subgenus from the Broka’s formula (II), including wherein R3 and R4 combine to form a pyrrole or pyrazole ring, because such structures are specifically disclosed by Broka in the same invention (see Broka’s Table 1, compounds 59, 61, 182, 215, 268 and 280).
The genus of compounds claimed in the method(s) of instant claims 10-12 fully encompasses the genus of instant claim 1, and is thus also anticipated by claims 1-4, 8 and 18 of Broka.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to W. JUSTIN YOUNGBLOOD whose telephone number is (703)756-5979. The examiner can normally be reached on Monday-Thursday from 8am to 5pm. The examiner can also be reached on alternate Fridays.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey S. Lundgren, can be reached at telephone number (571) 272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/W.J.Y./Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 2,4-Diamino-5-2′-isopropyl-4′-chloro-5′-methyl-phenoxy)pyrimidine
2 5-(6-isopropyl-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-7-yloxy)-pyrimidine-2,4-diamine
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