SUBSTITUTED CONDENSED AZINES AS ANTHELMINTIC COMPOUNDS

§103 §112

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 1-6 and 8-13 are currently pending. Priority The instant application claims priority as follows: PNG media_image1.png 104 524 media_image1.png Greyscale Continued Examination Under 37 CFR 1.114 A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 07/31/2026 has been entered. Receipt of arguments/remarks filed on 07/31/2026 is acknowledged. Applicant previously elected Group I, drawn to compounds and composition and compound 5, of formula PNG media_image2.png 186 262 media_image2.png Greyscale . Examination Search and examination have been extended to the compound scope of the prior art Hubsch et al. (WO 2018/087036) below. The examiner updated the prior art search regarding amide reversal in the chemical art. Therefore, the 103 rejection below. Subject matter of claims 1-6, 8 and 12 which is outside of the scope of the rejected compounds below, are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction requirement in the reply filed on 07/15/2025. Claims 9-11 and 13 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction requirement in the reply filed on 07/15/2025. Claims 1-6, 8 and 12 are the subject of this Office action. 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. Claim(s) 1-6, 8 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Hubsch et al. (WO 2018/087036) in view of Zitko et al. (Molecules 2018, 23, 2390), Yang et al. (J. Agric. Food Chem. 2019, 67, 13185-13194), and further in view of/as evidenced by US 7,214,677, WO2005/033103A1, Ruger (Tetrahedron 68 (2012) 8823-8829), Sulzer-Mosse et al. (Bioorganic & Medicinal Chemistry (2015), Vol 23 (9); p. 2129-2138), and Lamberth (Pest Manag Sci 2018;74:282-292). Applicant claims a compound of formula PNG media_image2.png 186 262 media_image2.png Greyscale and compounds of formula T-L-A (I) wherein T is T1, and Q is substituted substituted or unsubstituted phenyl. Determination of the Scope and Content of the Prior Art (MPEP §2141.01) Teachings of Hubsch et al. Hubsch teaches: PNG media_image3.png 172 648 media_image3.png Greyscale At page 2: PNG media_image4.png 210 716 media_image4.png Greyscale PNG media_image5.png 170 498 media_image5.png Greyscale . In at least page 47: PNG media_image6.png 380 600 media_image6.png Greyscale . Representative examples of the anthelmintic compounds of Hubsch wherein Q is fluoro-substituted phenyl and R2 is dimethylamino are found in Table 1 and are as follows: PNG media_image7.png 172 250 media_image7.png Greyscale , PNG media_image8.png 162 278 media_image8.png Greyscale , PNG media_image9.png 174 246 media_image9.png Greyscale , PNG media_image10.png 160 276 media_image10.png Greyscale (#30), PNG media_image11.png 174 246 media_image11.png Greyscale , PNG media_image12.png 164 276 media_image12.png Greyscale , PNG media_image13.png 160 278 media_image13.png Greyscale , PNG media_image14.png 162 272 media_image14.png Greyscale (#47), PNG media_image15.png 162 276 media_image15.png Greyscale (#49), PNG media_image16.png 158 276 media_image16.png Greyscale , PNG media_image17.png 202 248 media_image17.png Greyscale (#57), PNG media_image18.png 162 272 media_image18.png Greyscale (#81), PNG media_image19.png 164 276 media_image19.png Greyscale , PNG media_image20.png 200 244 media_image20.png Greyscale , PNG media_image21.png 170 270 media_image21.png Greyscale (#247) and PNG media_image22.png 170 248 media_image22.png Greyscale (#277). The compounds are efficacious against nematodes and their larvae. The list of secondary references is not exhaustive. The secondary references above show: 1) that the level of skill in the chemical art in regards to making and using reverse-amides is high, 2) that the skilled agrochemist had used amide-to-retroamide as a bioisosteric lead optimization strategy by 2012, 3) that the skilled agrochemist recognized the reversion of amide function as a well-known technique in lead optimization, and 4) that the artisan had a reasonable expectation of success in doing so. US 7,214,677 teaches “Benzamide, heteroarylamide and reverse amides” of formula PNG media_image23.png 98 96 media_image23.png Greyscale with the expectation of obtaining similar medicinal properties. WO2005/033103A1 teaches quinoline compounds of formula PNG media_image24.png 190 180 media_image24.png Greyscale for the treatment of inflammatory diseases. Amides and reverse-amides were prepared with the expectation of obtaining similar medicinal properties. See page 36. Amide: PNG media_image25.png 142 136 media_image25.png Greyscale Reverse-amide: PNG media_image26.png 144 132 media_image26.png Greyscale . Reversal produced biologically active compounds. See Table 1. Zitko disclosed: “Exchanging the amide moiety for a retro-amide is a strategy successfully used in medicinal chemistry and drug design. The obligatory textbook example is the group of local anesthetics. Cinchocaine is a substituted amide of a heteroaromatic acid, therefore having the -CONH- connecting bridge between the aromatic core and the basic amino moiety in the side chain. However, significantly more populated group of local anesthetics are anilides having the retro-amide -NHCO- linker (e.g., lidocaine, trimecaine, bupivacaine). In the field of antimicrobial research, the retro-amide modification led recently to derivatives with increased activity against Candida albicans [20]. The retro-amides of classical β-lactam antibiotics and their analogues were studied as substrates and/or inhibitors of beta-lactamases [21,22,23,24].” “Thus, the main aim of our study was to evaluate the effect of amide (-CONH-) vs retro-amide (-NHCO-) linker between the pyrazine and benzene core on in vitro antimycobacterial activity. Along with the linker exchange, we kept the variability both in the pyrazine core (R1 is H, 5-Cl, or 6-Cl) and in the benzene core (R2). Synthetic work was performed by two undergraduate students (co-authors of this paper, A.M. and O.V.) as a part of their diploma theses, therefore we kept the chemistry complexity at a suitable level.” “As a continued effort to extend the knowledge of SAR of N-phenylpyrazine-2-carboxamides as antimycobacterial agents, we designed a series of N-(pyrazin-2-yl)benzamides, which can be regarded retro-amide analogues (Figure 1).” PNG media_image27.png 152 556 media_image27.png Greyscale Figure 1. Design of title compounds inspired by previously published N-phenylpyrazine-2-carboxamides with antimycobacterial activity. Yang disclosed that in searching for novel fungicidal leads, fluxapyroxad derivatives were designed and synthesized by the inversion of carbonyl and amide groups. PNG media_image28.png 122 340 media_image28.png Greyscale Particularly, by 2012 Ruger used amide-to-retroamide substitution as a bioisosteric lead-optimization strategy in agrochemistry with the expectation of enhancing metabolic stability or activity. Particularly, by 2015 Sulzer-Mosse teaches that amide reversion is an actual lead-optimization strategy, applied to biologically active pesticide leads, and demonstrates that the reversed-amide products can remain highly biologically active. The motivation derives from the desire and expectation to further improve the physico-chemical properties of the lead pesticide 1. See pages 2129-2130: PNG media_image29.png 158 436 media_image29.png Greyscale PNG media_image30.png 164 551 media_image30.png Greyscale Analog 2 is as fungicidally active as 1 against the oomycete plant pathogens Phytophthora infestans and Plasmopara viticola down to the low concentration of 2 ppm. Particularly, Lamberth teaches that amide reversal is an established agrochemical lead-optimization strategy and provide concrete examples where reversal produced biologically active compounds. See page 286 and Figure 6. Ascertainment of the Difference Between the Prior Art and the Claims (MPEP §2141.012) The only difference between the compounds of the prior art cited above and claimed compounds of formula (I) is the replacement of the amide linker with a reverse-amide linker. That is, the amide (-CONH-) vs retro-amide (-NHCO-) linker between the quinoline and chromane core. The difference between the elected species and the tri-fluorinated compounds of Hubsch above is additionally, the position of a fluorine atom on the phenyl ring Q. Finding of prima facie obviousness--rational and motivation (MPEP §2142-2413) The level of ordinary skill in the art is high. Someone preparing these compounds would be trained in organic chemistry and would recognize the very close structural similarity and would expect these compounds to have similar properties. One of ordinary skill would have been motivated to make reverse-amide (-NHCO-) linker derivatives of the compounds of Hubsch above because the prior art demonstrated that amide reversal was an established lead-optimization technique and that, in multiple agrochemical programs, reversal successfully produced biologically active analogs. Thus, the skilled artisan had a reasonable basis to expect that the modification was worth trying and could preserve biological activity. Regarding the elected species of formula PNG media_image2.png 186 262 media_image2.png Greyscale , it would have been obvious to make the reverse-amide analog compound wherein Q is a 2,3,5-trifluorophenyl ring as in the elected species in view that Hubsch disclosed the compounds wherein Q is 2,3,6-trilfuorophenyl, 3,4,5-trifluorophenyl, 2,4,5-trifluorophenyl and 2,3,4-trilfuorophenyl as follows: PNG media_image21.png 170 270 media_image21.png Greyscale , PNG media_image14.png 162 272 media_image14.png Greyscale (#47), PNG media_image17.png 202 248 media_image17.png Greyscale (#57), and PNG media_image18.png 162 272 media_image18.png Greyscale (#81). The claimed compounds have exactly the same formula and the same use as the compounds of Hubsch; they are analogs possessing chemical and pharmacological similarities. There would have been a reasonable expectation of success due to that the prior at teaches how to prepare and use the compounds which share the same exact groups. In addition, MPEP 2144.09 states: A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979). See In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963) and In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990) for an extensive review of the case law pertaining to obviousness based on close structural similarity of chemical compounds. See also MPEP § 2144.08, subsection II.A.4.(c) and (d). Under the Supreme Court rationales in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 127 S. Ct. 1727, 82 USPQ2d 1385, 1395-97 (2007), here at least exemplary rationales (A) through (D) apply: (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. The examiner has reconsidered the patentability of the claimed invention. Applicant’s arguments have been carefully considered but were found unpersuasive. Applicant arguments are directed to that the prior art Zitko and Yang teach away from the retro-amide modification and do not provide a reasonable expectation of success because most of the retro-amides possessed lower or no activity compared to the corresponding carboxamides and because Zitko further states that the inversion usually leads to a loss or decrease of in vitro antimycobacterial activity. The examiner has cited additional references that represent/evidence the state of the art at the time of filing. The references teach that amide reversal is an established agrochemical lead-optimization strategy and provide concrete examples where reversal produced biologically active compounds. Currently, a preponderance of the evidence supports the Examiner’s position that the skilled artisan had a reasonable basis to expect that the modification was worth trying and could preserve biological activity, even though success was not guaranteed. Regarding that the rejection of the elected species requires multiple simultaneous modifications, the rejection of the elected species requires the motivation to make two modifications to any of the four examples of Hubsch above. The modifications are, the position of one of the three fluoro atoms on the phenyl ring, and the reversal of the amide embedded within the two rings. Hubsch taught the modification of moving a third fluoro from different positions on the phenyl ring, therefore, providing guidance and motivation to do so. The reversal of the amide was taught by the secondary references. 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 1-6, 8 and 12 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 and 11 of U.S. Patent No. 10,889,573 in view of Zitko et al. (Molecules 2018, 23, 2390), Yang et al. (J. Agric. Food Chem. 2019, 67, 13185-13194), and further in view of/as evidenced by US 7,214,677, WO2005/033103A1, Ruger (Tetrahedron 68 (2012) 8823-8829), Sulzer-Mosse et al. (Bioorganic & Medicinal Chemistry (2015), Vol 23 (9); p. 2129-2138), and Lamberth (Pest Manag Sci 2018;74:282-292) as above. Although the claims at issue are not identical, they are not patentably distinct from each other because the compounds and compositions as claimed in the rejected claims are prima facie obvious over claims 1-6 and 11 of the patent. The disclosure of the patent teaches the particular compounds that represent patented claims 1-6 and 11. Examples of the anthelmintic compounds wherein Q is fluoro-substituted phenyl and R2 is dimethylamino are found in Table 1 of the patent as described above and are particular embodiments of the invention claimed in the reference patent. Ascertainment of the difference between the conflicting application and the claims. (MPEP §2141.02) The instant claims differ from the conflicting patented claims in the replacement of the amide linker with a reverse-amide linker (that is the amide (-CONH-) vs retro-amide (-NHCO-) linker between the quinoline and chromane core for the examples of the compounds covered by the patented claims. Finding of prima facie obviousness--rational and motivation. (MPEP §2142-2413) What is covered by the patented claims was exemplified in the patent. One of ordinary skill would have been motivated to make reverse-amide (-NHCO-) linker derivatives of the compounds of Hubsch above because the prior art demonstrated that amide reversal was an established lead-optimization technique and that, in multiple agrochemical programs, reversal successfully produced biologically active analogs. Thus, the skilled artisan had a reasonable basis to expect that the modification was worth trying and could preserve biological activity. Regarding the elected species of formula PNG media_image2.png 186 262 media_image2.png Greyscale , it would have been obvious to make the reverse-amide analog compound wherein Q is a 2,3,5-trifluorophenyl ring as in the elected species in view that the patent disclosed the compounds wherein Q is 2,3,6-trilfuorophenyl, 3,4,5-trifluorophenyl, 2,4,5-trifluorophenyl and 2,3,4-trilfuorophenyl as follows: PNG media_image21.png 170 270 media_image21.png Greyscale , PNG media_image14.png 162 272 media_image14.png Greyscale (#47), PNG media_image17.png 202 248 media_image17.png Greyscale (#57), and PNG media_image18.png 162 272 media_image18.png Greyscale (#81). The claimed compounds have exactly the same formula and same use as the patented compounds. In addition, MPEP 2144.09 states: A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979). See In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963) and In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990) for an extensive review of the case law pertaining to obviousness based on close structural similarity of chemical compounds. See also MPEP § 2144.08, This rejection is proper under MPEP 804 II. B. 2. (a): Further, those portions of the specification which provide support for the reference claims may also be examined and considered when addressing the issue of whether a claim in the application defines an obvious variation of an invention claimed in the reference patent or application (as distinguished from an obvious variation of the subject matter disclosed in the reference patent or application). In re Vogel, 422 F.2d 438, 441-42, 164 USPQ 619, 622 (CCPA 1970). The court in Vogel recognized "that it is most difficult, if not meaningless, to try to say what is or is not an obvious variation of a claim," but that one can judge whether or not the invention claimed in an application is an obvious variation of an embodiment disclosed in the patent or application which provides support for the claim. According to the court, one must first "determine how much of the patent disclosure pertains to the invention claimed in the patent" because ONLY "[t]his portion of the specification supports the patent claims and may be considered." The court pointed out that "this use of the disclosure is not in contravention of the cases forbidding its use as prior art, nor is it applying the patent as a reference under 35 U.S.C. 103, since only the disclosure of the invention claimed in the patent may be examined." In AbbVie Inc. v. Kennedy Institute of Rheumatology Trust, 764 F.3d 1366, 112 USPQ2d 1001 (Fed. Cir. 2014), the court explained that it is also proper to look at the disclosed utility in the reference disclosure to determine the overall question of obviousness in a nonstatutory double patenting context. See Pfizer, Inc. v. Teva Pharm. USA, Inc., 518 F.3d 1353, 86 USPQ2d 1001 (Fed. Cir. 2008); Geneva Pharmaceuticals Inc. v. GlaxoSmithKline PLC, 349 F3d 1373, 1385-86, 68 USPQ2d 1865, 1875 (Fed. Cir. 2003). Applicant’s arguments are the same as for the 103 rejection above. Thus, the examiner’s response to arguments above is incorporate herein. 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 1-6, 8 and 12 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. In Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc), the Federal Circuit noted the importance of an application's disclosure and stated, “the hallmark of written description is disclosure.” A disclosure adequately describes an invention when it “reasonably conveys to those skilled in the art that the inventor had possession of the claimed subject matter as of the filing date.” Id. at 1351. “A ‘mere wish or plan' for obtaining the claimed invention is not adequate written description.” Centocor Ortho Biotech, Inc. v. Abbott Labs, 636 F.3d 1341, 1348 (Fed. Cir. 2011). The Federal Circuit explained what is required to meet the written description requirement in Ariad Pharm., Inc. v. Eli Lilly & Co.: This inquiry, as we have long held, is a question of fact. Ralston Purina, 772 F.2d at 575. Thus, we have recognized that determining whether a patent complies with the written description requirement will necessarily vary depending on the context. Capon v. Eshhar, 418 F.3d 1349, 1357-58 (Fed. Cir. 2005). Specifically, the level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology. Id. For generic claims, we have set forth a number of factors for evaluating the adequacy of the disclosure, including “the existing knowledge in the particular field, the extent and content of the prior art, the maturity of the science or technology, [and] the predictability of the aspect at issue.” Id. at 1359. The Federal Circuit reflected on Eli Lilly in Ariad while explaining how to sufficiently describe a genus of compounds: We held that a sufficient description of a genus instead requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can “visualize or recognize” the members of the genus. Id. at 1568-69. We explained that an adequate written description requires a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials. Id. at 1568 (quoting Fiers v. Revel, 984 F.2d 1164, 1171 (Fed. Cir. 1993)). We have also held that functional claim language can meet the written description requirement when the art has established a correlation between structure and function. See Enzo, 323 F.3d at 964 (quoting 66 Fed. Reg. 1099 (Jan. 5, 2001)). But merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing that one has invented a genus and not just a species. Where, as here, the claims cover a broad genus, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are “representative of the full variety or scope of the genus” per MPEP 2163, or by the establishment of “a reasonable structure-function correlation.” AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that “only describe[d] one type of structurally similar antibodies” that “are not representative of the full variety or scope of the genus.”). A "representative number of species" must represent the entire claimed genus and account for variation between the species of the genus. [A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated. Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004). The instant claims are drawn to Formula (I) PNG media_image31.png 24 64 media_image31.png Greyscale , wherein PNG media_image32.png 348 542 media_image32.png Greyscale L is selected from PNG media_image33.png 242 464 media_image33.png Greyscale , A is A1 or A2, PNG media_image34.png 132 262 media_image34.png Greyscale PNG media_image35.png 250 590 media_image35.png Greyscale PNG media_image36.png 18 220 media_image36.png Greyscale R1 is selected from the group consisting of hydrogen, cyano, -CHO, -OH, C1-C4-alkyl, C1-C4- halogenoalkyl having 1 to 5 halogen atoms, CI-C4-alkoxy, C1-C4-halogenoalkoxy having 1 to 5 halogen atoms, C3-C6-cycloalkyl, C3-C6-halogenocycloalkyl having 1 to 5 halogen atoms, C3-C4- alkenyl, C3-C4-alkynyl, CI-C4-alkoxy-C1-C4-alkyl, C3-C6-cycloalkyl-C1-C3- alkyl, cyano-C1-C4- alkyl, -NH-CI-C4-alkyl, -N(CI-C4-alkyl)2 PNG media_image37.png 16 10 media_image37.png Greyscale NH2-C1-C4-alkyl-, C1-C4- alkyl-NH-C1-C4-alkyl-, (C1- C4-alkyl)2N-C1-C4-alkyl-, CI-C4-alkyl-C(O)-, C1-C4- halogenoalkyl-C(O)- having 1 to 5 halogen atoms, CI-C4-alkoxy-C(O)-, benzyloxy-C(O)-, CI-C4-alkoxy-C1-C4-alkyl-C(O)-, -SO2-CI-C4-alkyl, and -SO2-C1-C4-halogenoalkyl having 1 to 5 halogen atoms; phenyl-C1-C4-alkyl, optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of halogen, -OH, -NO2, cyano, C1-C4-halogenoalkyl having 1 to 5 halogen atoms, C1-C4-alkoxy, CI-C4-halogenoalkoxy having 1 to 5 halogen atoms, -NH2, -NH(C1- C4-alkyl), -N(C1-C4-alkyl)2 PNG media_image37.png 16 10 media_image37.png Greyscale -S-CI-C4-alkyl, -S(O)-C1-C4-alkyl,-SO2-CI-C4-alkyl, -S-CI-C4-halogenoalkyl having 1 to 5 halogen atoms, -S(O)-C1-C4- halogenoalkyl having 1 to 5 halogen atoms and -SO2-C1-C4-halogenoalkyl having 1 to 5 halogen atoms; heterocyclyl-C1-C4-alkyl, wherein the heterocyclyl substituent is selected from the group consisting of 4- to 10-membered heterocycloalkyl, 5-membered heteroaryl and 6- membered heteroaryl, each of which is optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halogen, -OH, -NO2, cyano, C1-C4- halogenoalkyl having 1 to 5 halogen atoms, C1- C4-alkoxy, CI-C4-halogenoalkoxy having 1 to 5 halogen atoms, -NH2, -NH(CI-C4-alkyl), -N(C1- C4-alkyl)2, -S-CI-C4-alkyl, -S(O)- C1-C4-alkyl, -SO2-C1-C4-alkyl, -S-C1-C4-halogenoalkyl having 1 to 5 halogen atoms, - S(O)-C1-C4-halogenoalkyl having 1 to 5 halogen atoms and -SO2-C1-C4- halogenoalkyl having 1 to 5 halogen atoms, R2 is selected from the group consisting of hydrogen, halogen, cyano, -COOH, CI-C4-alkoxy-C(O)-, -C(O)-NH2, -C(O)-NH(C1-C4- alkyl), - C(O)-N(CI-C4-alkyl)2, -OR14;-SR15, -S(O)R15, -SO2R15;C1-C6-alkyl, C3-C6-cycloalkyl, C2-C4-alkenyl, C3-C6-cycloalkenyl, C2-C4-alkynyl or phenyl-C1-C4- alkyl, each of which is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of halogen, -OH, -NO2, cyano, C1-C4- alkyl-C(O)-, CI-C4-alkoxy-C(O)-,-C(O)-NH2, -C(O)-NH(C1-C4-alkyl), -C(O)-N(C1-C4-alkyl)2 PNG media_image37.png 16 10 media_image37.png Greyscale C1-C4-alkyl, C1-C4- halogenoalkyl having 1 to 5 halogen atoms, CI-C4-alkoxy, -NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, -S-C1-C4- alkyl, -S(O)-C1-C4-alkyl, -SO2-C1-C4-alkyl, -S-C1-C4-halogenoalkyl having 1 to 5 halogen atoms, -S(O)-CI-C4-halogenoalkyl having 1 to 5 halogen atoms and -SO2-C1-C4-halogenoalkyl having 1 to 5 halogen atoms;heterocyclyl-C1-C4-alkyl, wherein the heterocyclyl substituent is selected from the group consisting of 4- to 10-membered heterocycloalkyl, 5-membered heteroaryl and 6- membered heteroaryl, each of which is optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halogen, -OH, -NO2, cyano, C1-C4- halogenoalkyl having 1 to 5 halogen atoms, C1- C4-alkoxy, CI-C4-halogenoalkoxy having 1 to 5 halogen atoms, -NH2, -NH(CI-C4-alkyl), -N(C1- C4-alkyl)2, -S-CI-C4-alkyl, -S(O)- CI-C4-alkyl, -SO2-CI-C4-alkyl, -S-CI-C4-halogenoalkyl having 1 to 5 halogen atoms, -S(O)- C1-C4-halogenoalkyl having 1 to 5 halogen atoms and -SO2-C1-C4- halogenoalkyl having 1 to 5 halogen atoms;phenyl which is optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, -OH, C1-C4-alkyl, C1-C4-halogenoalkyl having 1 to 5 halogen atoms, C1-C4-alkoxy, CI-C4-halogenoalkoxy having 1 to 5 halogen atoms, C3-C6- cycloalkyl, -NH2, -NH(CI-C4-alkyl), -N(CI-C4-alkyl)2 PNG media_image37.png 16 10 media_image37.png Greyscale -S-CI-C4-alkyl, - S(O)-C1-C4-alkyl, -SO2- C1-C4-alkyl, -S-CI-C4-halogenoalkyl having 1 to 5 halogen atoms,-S(O)-C1-C4-halogenoalkyl having 1 to 5 halogen atoms and -SO2-C1-C4-halogenoalkyl having 1 to 5 halogen atoms; anda monocyclic or a bicyclic heterocycle selected from the group consisting of 4- to 10- membered heterocycloalkyl, heterospirocycloalkyl, 5-membered heteroaryl and 6- membered heteroaryl, each of which is optionally substituted by 1, 2, 3 or 4 substituents independently selected from the group consisting of halogen, cyano, nitro, -OH, oxo, thiono, -COOH, C1-C4-alkoxy-C(O)-, -C(O)-NH2, - C(O)-NH(C1-C4-alkyl), -C(O)-N(C1- C4-alkyl)2, C1-C4-alkyl, CI-C4-alkyl-C(O)--, C1-C4- halogenoalkyl having 1 to 5 halogen atoms, C1-C4-alkoxy, hydroxy-C1-C4-alkyl, C1-C4- alkoxy-C1- C4-alkyl-, CI-C4-halogenoalkoxy having 1 to 5 halogen atoms, C3-C6- cycloalkyl, -NH2, -NH(C1- C4-alkyl), -N(C1-C4-alkyl)2 PNG media_image37.png 16 10 media_image37.png Greyscale -S-C1-C4-alkyl, -S(O)-CI-C4- alkyl, -SO2-CI-C4-alkyl, -S-C1-C4- halogenoalkyl having 1 to 5 halogen atoms, -S(O)-C1-C4-halogenoalkyl having 1 to 5 halogen atoms, -SO2-C1-C4-halogenoalkyl having 1 to 5 halogen atoms, and 4- to 10- membered heterocycloalkyl, R3 is selected from the group consisting ofhydrogen, halogen or C1-C4-alkyl, R4 is selected from the group consisting of hydrogen, halogen, -OH, cyano, CI-C4-alkyl, C3-C6- cycloalkyl, C1-C4-halogenoalkyl having 1 to 5 halogen atoms, C1-C4-alkoxy-C1-C4-alkyl, C1-C4- alkoxy, C1-C4-alkyl-C(O)-, -NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2 PNG media_image37.png 16 10 media_image37.png Greyscale -S-C1-C4- alkyl, -S(O)-C1-C4-alkyl, -SO2-C1-C4-alkyl, R5 is selected from the group consisting of hydrogen, halogen, -OH, cyano, CI-C4-alkyl, C3-C6- cycloalkyl, C1-C4-halogenoalkyl having 1 to 5 halogen atoms, C1-C4-alkoxy-C1-C4-alkyl, C1-C4- alkoxy, C1-C4-alkyl-C(O)-, -NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2 PNG media_image37.png 16 10 media_image37.png Greyscale -S-C1-C4- alkyl, -S(O)-C1-C4-alkyl, -SO2-C1-C4-alkyl, R6 is selected from the group consisting of hydrogen, halogen, -OH, cyano, CI-C4-alkyl, C3-C6- cycloalkyl, C1-C4-halogenoalkyl having 1 to 5 halogen atoms, C1-C4-alkoxy-C1-C4-alkyl, C1-C4- alkoxy, C1-C4-alkyl-C(O)-, -NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2 PNG media_image37.png 16 10 media_image37.png Greyscale -S-C1-C4- alkyl, -S(O)-C1-C4-alkyl, -SO2-C1-C4-alkyl, R7 is selected from the group consisting of hydrogen, -OH, halogen, C1-C4-alkyl and C1-C4- alkoxy, R8 is selected from the group consisting of hydrogen, -OH, halogen, C1-C4-alkyl and C1-C4- alkoxy, or R7 and R8 form, together with the carbon atom to which they are attached, a 3- to 6-membered ring selected from the group consisting of C3-C6-cycloalkyl and 3- to 6-membered heterocycloalkyl, or R7 and R8 together form an oxo group (=O), R9 is selected from the group consisting of hydrogen, C1-C4-alkyl, CI-C4-halogenoalkyl having 1 to 5 halogen atoms and C1-C4-alkoxy, R10 is selected from the group consisting of hydrogen, -OH, CI-C4-alkyl and C1-C4-alkoxy, R11 is selected from the group consisting of hydrogen, C1-C4-alkyl and C1-C4-alkoxy, or R10 and R11 form, together with the carbon atom to which they are attached, a 3- to 6- membered ring selected from the group consisting of C3-C6-cycloalkyl and 3- to 6- membered heterocycloalkyl, PNG media_image38.png 94 584 media_image38.png Greyscale PNG media_image39.png 274 586 media_image39.png Greyscale PNG media_image40.png 196 538 media_image40.png Greyscale By contrast, the specification exemplifies only 13 compounds (+2 enantiomers) corresponding to the claimed genus: PNG media_image41.png 98 144 media_image41.png Greyscale , PNG media_image42.png 104 144 media_image42.png Greyscale , PNG media_image43.png 100 142 media_image43.png Greyscale , PNG media_image44.png 100 142 media_image44.png Greyscale , PNG media_image45.png 170 232 media_image45.png Greyscale , PNG media_image46.png 206 236 media_image46.png Greyscale PNG media_image47.png 198 236 media_image47.png Greyscale , PNG media_image48.png 108 152 media_image48.png Greyscale , PNG media_image49.png 134 188 media_image49.png Greyscale , PNG media_image50.png 108 154 media_image50.png Greyscale , PNG media_image51.png 140 154 media_image51.png Greyscale , PNG media_image52.png 134 158 media_image52.png Greyscale , PNG media_image53.png 114 164 media_image53.png Greyscale , PNG media_image54.png 172 234 media_image54.png Greyscale and PNG media_image55.png 170 234 media_image55.png Greyscale . These few species are all very structurally close to each other. These few species cannot possibly represent the entire genus claimed or account for all of the variation between species of such a genus. For example, while the claimed genus of compounds encompasses compounds wherein L represents PNG media_image56.png 56 94 media_image56.png Greyscale , PNG media_image57.png 88 82 media_image57.png Greyscale or PNG media_image58.png 52 78 media_image58.png Greyscale , and others, the specification only provides support for group of formula PNG media_image59.png 80 88 media_image59.png Greyscale . Further, while the claimed genus encompasses Q being a substituted or unsubstituted aryl or heteroaryl as recited above, the specification only provides support for halo-substituted phenyl. In addition, while the claimed genus encompasses compounds wherein A is A1 or A2, PNG media_image34.png 132 262 media_image34.png Greyscale and X and Y are each CR7R8, O, S, and N-R9, wherein at least one is CR7R8, or wherein X, Y form together a ring member selected from -C(O)-O-, -C(O)-NR9-, -S(O)-NR9-, SO2-NR9- and -SO2-O-, the specification only provides support for A being the group PNG media_image60.png 62 50 media_image60.png Greyscale or PNG media_image61.png 60 54 media_image61.png Greyscale . Even when considered in context of the entire disclosure, support for the entire genus cannot be afforded. Substantial structural variations exist in the genus embraced by the claimed formula (I). However, the disclosure of species supporting the genus is limited to the above species, which all have the same particular T, Q, L and A groups. Support for the entirety of the claimed genus and its alleged use cannot be extrapolated from the 13 species exemplified for the genus. Chemistry and biotechnology are generally considered to be unpredictable and/or have unpredictable factors. See, e.g., In re Carleton, 599 F.2d 1021, 202 USPQ 165, 170 (CCPA 1979) ("Although there is a vast amount of knowledge about general relationships in the chemical arts, chemistry is still largely empirical, and there is often great difficulty in predicting precisely how a given compound will behave.”). The pharmaceutical art, that is the use of a chemical compound to affect a desired physiological activity, is generally considered to be unpredictable and/or have unpredictable factors. See, e.g., In re Fisher, 427 F.2d 833, 839 (CCPA 1970) (“In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved (emphasis added); In re Bowden, 183 F.2d 115, 86 USPQ 419, 423 (“chemical reactions frequently are unpredictable”). Considering the unpredictability found in chemistry and biotechnology, accordingly, when a claim presents a genus with substantial variation as that currently presented by Applicant, the disclosure must adequately reflect such variation with a representative number of species. The lack of any disclosure of examples may be considered in determining whether a claimed invention was adequately described. Boston Scientific Corp. v. Johnson & Johnson, 647 F.3d 1353 (Fed. Cir. 2011). The species described in the specification do not cover the entire genus such that it is a representative sample of the genus as the species are close together in structure and only describe an extremely small portion of the claimed genus. Therefore, the claims lack written description and are properly rejected under 35 U.S.C. 112(a). Conclusion Claims 1-6, 8 and 12 are rejected. Not every piece of prior art found in the search has been applied against the instant claims. See MPEP 904.03. 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To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /VALERIE RODRIGUEZ-GARCIA/Primary Examiner, Art Unit 1621