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. DETAILED ACTION Claims 1 - 3, 15, 21, 28, 50, 51, 62, 63, 90, 91, 98, 101, 102, 128, 133, 137, 153, 154, 158, 165 - 168, 170, 172, 180, 184 and 185 are pending in the application and are under examination. Claim Ob jections Claims 62 and 90 are objected to for reciting multiple instance of “Wherein”. These should be changed to “wherein” such that “wherein” is not capitalized. Claim Rejections - 35 USC § 112 The following is a quotation of 35 U.S.C. 112(b): (b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention. The following is a quotation of 35 U.S.C. 112 (pre-AIA), second paragraph: The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention. Claim s 1 - 3, 15, 21, 50, 51, 62, 63, 90, 91, 98, 101, 102, 128, 133 and 137 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention. A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) is considered indefinite, since the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). Note the explanation given by the Board of Patent Appeals and Interferences in Ex parte Wu , 10 USPQ2d 2031, 2033 (Bd. Pat. App. & Inter. 1989), as to where broad language is followed by "such as" and then narrow language. The Board stated that this can render a claim indefinite by raising a question or doubt as to whether the feature introduced by such language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Note also, for example, the decisions of Ex parte Steigewald , 131 USPQ 74 (Bd. App. 1961); Ex parte Hall , 83 USPQ 38 (Bd. App. 1948); and Ex parte Hasche , 86 USPQ 481 (Bd. App. 1949). In the present instance , claim 1 recites the language “ optionally ”, so it is unclear if the narrow limitation actually further limits the claim . For example, claim 2 recites a limitation of a limitation that occurs after the “optionally” language, so it is unclear if claim 2 limits claim 1 and if Applicant intends claim 1 to comprise a second antigen binding domain. Accordingly, due to the ambiguity that results from a broad limitation followed by a narrow limitation used in this claim, the claim fails to delineate the metes and bounds of the subject matter regarded as the invention with the clarity and particularity necessary to satisfy the requirement set forth under 35 U.S.C. § 112, second paragraph, so as to permit the skilled artisan to know or determine infringing subject matter. Claim 172 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention. A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) is considered indefinite, since the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). Note the explanation given by the Board of Patent Appeals and Interferences in Ex parte Wu , 10 USPQ2d 2031, 2033 (Bd. Pat. App. & Inter. 1989), as to where broad language is followed by "such as" and then narrow language. The Board stated that this can render a claim indefinite by raising a question or doubt as to whether the feature introduced by such language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Note also, for example, the decisions of Ex parte Steigewald , 131 USPQ 74 (Bd. App. 1961); Ex parte Hall , 83 USPQ 38 (Bd. App. 1948); and Ex parte Hasche , 86 USPQ 481 (Bd. App. 1949). In the present instance , claim 172 recites the language “ such as ”, so it is unclear if the narrow limitation after the “such as” phrase actually further limits the claim . Accordingly, due to the ambiguity that results from a broad limitation followed by a narrow limitation used in this claim, the claim fails to delineate the metes and bounds of the subject matter regarded as the invention with the clarity and particularity necessary to satisfy the requirement set forth under 35 U.S.C. § 112, second paragraph, so as to permit the skilled artisan to know or determine infringing subject matter. Claim 91 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention. Claim 91 is indefinite in the recitation of “ Lb1 " , “Lc1” and “Lc2” because it is unclear what these designations refer to. Notably, the other parts of the formula are defined in the claim, but these variables are not so it is unclear what they refer to. Accordingly, the metes and bounds of the claim cannot be properly determined and the invention is not set forth with the clarity and particularity necessary to satisfy the requirement set forth 35 U.S.C. 112, second paragraph , so as permit the skilled artisan to know or determine infringing subject matter . Claim 1 0 2 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention. Claim 102 indefinite in the recitation of “ the linker " because the claims from which it depends do not recite a linker. Therefore, the recitation lacks proper antecedent basis and it cannot be determined which (if any) linker is being referred to. Accordingly, the metes and bounds of the claim cannot be properly determined and the invention is not set forth with the clarity and particularity necessary to satisfy the requirement set forth 35 U.S.C. 112, second paragraph , so as permit the skilled artisan to know or determine infringing subject matter. Claim 101 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention. The claim is indefinite because the claim recites mutations at various positions without providing a sequence with those positions or a numbering system used to identify the positions. For example, various different numbering systems can be used to number an antibody so that unless a sequence or numbering system is present, it is unclear which position is being refer r ed to. Therefore , the claim fail s to delineate the metes and bounds of the subject matter that Applicant regards as the invention with the requisite clarity and particularity to permit the skilled artisan to know or determine infringing subject matter. The following is a quotation 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 35 U.S.C. 112 (pre-AIA), first paragraph: 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 - 3, 15, 21, 51, 62, 63, 90, 91, 98, 101, 102, 128, 133 , 137 , 184 and 185 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection. “[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co. , 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention . Vas-Cath, Inc. v. Mahurkar , 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04. For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly , 43 USPQ2d 1398 (CAFC 1997). “[A] sufficient description of a genus . . . 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.” Ariad , 598 F.3d at 1350 (quoting Eli Lilly , 119 F.3d at 1568-69). A “representative number of species” means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech , 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention. For example, the Federal Circuit has found that possession of a mouse antibody heavy and light chain variable regions provides a structural "stepping stone" to the corresponding chimeric antibody, but not to human antibodies. Centocor Ortho Biotech Inc. v. Abbott Labs. , 97 USPQ2d 1870, 1875 (Fed. Cir. 2011). The teachings of the specification and the claimed invention: The nature and scope of the claimed invention at issue is a genus of single domain antibodies that bind to D2 (see claim 1), PD-1 (see claim 184) or CD47 (see claim 185) that can comprise variable CDR sequences because of the 8 0% identical language (see e.g., claim s 1 , 137. 184 and 185). This variability allows over 20 amino acid changes in the claimed CDRs from sequences SEQ ID Nos: 7, 14, 21, 28, 35, 42, 49, 56 , 63 and 70. The specification discloses in the examples isolating single domain antibody clones that bind these antigens that have specific CDR sequences as set forth in Tables 3-5 over pages 135-138). However, the specification does not disclose making any variations in these CDR s which retain binding to any of these antigens . State of the Art It is established in the art that single domain antibodies comprise 3 CDRs involved in antigen binding and these CDRs are variable regions that differ in sequence and are selected to bind an antigen (see Muyldermans et al (ARB:82:775-797, 2013, entire document, e.g., 777-780). There is no evidence in the art or the specification combinations of residues can be altered as set forth in the instant claims and retain binding. The teachings from Muyldermans et al highlight that a skill artisan cannot recognize or predict that CDR s from one single domain antibody can be altered and retain binding. Claim Analysis A skilled artisan would recognize that the specificity of a single domain antibody is dependent upon its three specific CDR sequences. The instant specification discloses clones that are sufficient for antigen-binding specificity to D2 , PD-1 or CD47 based on specific CDR sequences , but does not identify that other CDR combinations or variations encompassed by the claims retain binding. Notably, the claims encompass thousands of antibodies which have not been determined to bind these antigens . As discussed above, single domain antibodies comprise 3 CDRs involved in antigen binding and these CDRs are variable regions, but one cannot envision which other sets of CDRs encompassed by the claims will bind to these antigens . It is noted that, “[r]egardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to the subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds , or infringing methods from non-infringing methods.” University of Rochester v. G.D. Searle Co. , 69 USPQ2d 1886 1984 (CAFC 2004) (emphasis added). In this case, a skilled artisan cannot visualize CDRs in a single domain antibody that binds to VEGFA other than the sets of 3 CDRs from the two clones . The disclosure therefore does not show that applicant was in possession of the necessary common attributes or features possessed by the members of the claimed genus. Accordingly, the skilled artisan would not recognize that applicants were in possession of the invention as broadly claimed at the time the application was filed. Claim s 170 and 172 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for using methods such as treating D2 expressing cancers comprising administering to a subjec t a n effective amount of the composition of claim 158 does not reasonably provide enablement for using the full scope of the claimed methods such as treating all diseases or disorders or cancer that do not express D2 . 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. MPEP § 2164.01 states: The standard for determining whether the specification meets the enablement requirement was cast in the Supreme Court decision of Mineral Separation v. Hyde , 242 U.S. 261, 270 (1916) which postured the question: is the experimentation needed to practice the invention undue or unreasonable? That standard is still the one to be applied. In re Wands , 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). Accordingly, even though the statute does not use the term "undue experimentation," it has been interpreted to require that the claimed invention be enabled so that any person skilled in the art can make and use the invention without undue experimentation. In re Wands , 858 F.2d at 737, 8 USPQ2d at 1404 (Fed. Cir. 1988). There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue”. These factors, which have been outlined in the Federal Circuit decision of In re Wands , 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), include, but are not limited to, the nature of the invention, the state of the prior art, the relative skill of those in the art, the amount of direction or guidance disclosed in the specification, the presence or absence of working examples, the predictability or unpredictability of the art, the breadth of the claims, and the quantity of experimentation which would be required in order to practice the invention as claimed. See also Ex parte Forman , 230 USPQ 546 (BPAI 1986). The amount of guidance, direction, and exemplification disclosed in the specification, as filed, would not be sufficient to enable the skilled artisan to make and/or use the claimed invention at the time the application was filed without undue and/or unreasonable experimentation. With respect to treating all diseases or disorders , it is noted that the art of Bonuccelli et al (Parkinsonism and Related Disorders, 15S:s44-s53, 2009 ) discloses that D2 agonists have been used to treat P a rkinson ’s disease (see page s45 ). Accordingly, it does not appear that antibodies that kill or inhibit the growth of D2 expressing cells (see Figures) would treat all diseases or disorders as claimed . Therefore, one of skill in the art would be subject to undue experimentation to determine how to treat any and all diseases , because diseases include diseases where it is unlikely the claimed agent would be effective. Notably, in this case the specification only presents evidence that that antibodies of claim 153 are effective in treating cancers that express D2 (see Figures and Examples), so one would also be subject to treat cancers that do not express D2 with the claimed agent. I n this case, the specification presents merely prophetic language that the recited compositions would be effective to treat all disorders and diseases and those diseases of claim 172 . As such, the specification, which lacks any specific non-general guidance, direction, and exemplification that is reasonably commensurate in scope with the intended use of treat ing all disorders and diseases and those diseases of claim 172 , would not reasonably enable the artisan to prevent such diseases without undue and/or unreasonable experimentation. Here, there is no disclosure of testing using any model to determine if any of the claimed antibodies as claimed can treat all disorders and disease and the diseases of claim 172 ; again, the assertion that the invention is useful is based solely upon merely prophetic examples . Applicant is reminded that reasonable correlation must exist between the scope of the claims and scope of enablement set forth. In deciding In re Fisher , 166 USPQ 18, 24 (CCPA 1970), the Court indicated the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute. “Tossing out the mere germ of an idea does not constitute enabling disclosure. While every aspect of a generic claim certainly need not have been carried out by an inventor, or exemplified in the specification, reasonable detail must be provided in order to enable members of the public to understand and carry out the invention.” Genentech Inc. v. Novo Nordisk A/S , 42 USPQ2d 1001, 1005 (CA FC 1997). In conclusion, upon careful consideration of the factors used to determine whether undue experimentation is required, in accordance with the Federal Circuit decision of In re Wands , 858 F.2d at 737, 8 USPQ2d at 1404 (Fed. Cir. 1988), the amount of guidance, direction, and exemplification disclosed in the specification, as filed, is not deemed sufficient to have enable the skilled artisan to make and/or use the claimed invention at the time the application was filed without undue and/or unreasonable experimentation. Improper Markush Grouping Claims 1 - 3, 15, 21, 28, 50, 51, 62, 63, 90, 91, 98, 101, 102, 128, 133, 137, 153, 154, 158, 165 - 168, 170, 172 and 180, are rejected on the judicially-created basis that it contains an improper Markush grouping of alternatives. See In re Harnisch , 631 F.2d 716, 721-22 (CCPA 1980), Ex parte Hozumi , 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984) (Federal Register; Vol. 76, No. 27, Page 7166, February 9, 2011) . The improper Markush grouping includes species of the claimed invention that do not share both a substantial structural feature and a common use that flows from the substantial structural feature. The members of the improper Markush grouping do not share a substantial feature and/or a common use that flows from the substantial structural feature for the following reasons : The claims encompass multiple independent clones that bind to D2 and other claims that recite antibodies comprising such multiple independent clones . Notably, claim 1 recites sequences from eight independent clones . As evidenced by Muyldermans ( supra ) the antigen-combining site of a VHH antibody is a three-dimensional structure, which fully comprises three “complementarity-determining regions” (CDRs), which determine much of antibody's antigen-binding specificity. Accordingly, the substantial structural feature of a VHH antibody is the three CDRs of the antibody which determine much of antibody's antigen-binding specificity. Consequently, every antibody with different CDR sequences has a different substantial structural feature because different amino acids in the binding domains would bind to the antigen . Therefore, because the Markush Groups in the claims each recite single domain antibodies with CDR sequences from different clones and the antibodies otherwise do not appear to contain any substantial structural feature, it is submitted that the members of the Markush groupings do not share a substantial structural feature as required . For example, CDR3 of antibody KC001 (SEQ ID NO:3) and CDR3 of antibody KC00 3 (SEQ ID NO: 17 ) (see page 135) have very different sequences that do not have any similarity . Accordingly, the Markush groups do not share a substantial structural feature and are improper for that reason . In response to this rejection, Applicant should either amend the claim(s) to recite only individual species or grouping of species that share a substantial structural feature as well as a common use that flows from the substantial structural feature, or present a sufficient showing that the species recited in the alternative of the claims(s) in fact share a substantial structural feature as well as a common use that flows from the substantial structural feature. This is a rejection on the merits and may be appealed to the Board of Patent Appeals and Interferences in accordance with 35 U.S.C. §134 and 37 CFR 41.31(a)(1) (emphasis provided). In this case, it is suggested that Applicant amend the claims to remove multiple independent clones from the claims to obviate this rejection. Applicant is invited to submit new independent claims that are drawn each different clone , if so desired. 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 - 3, 15, 21, 28, 50, 51, 62, 63, 90, 91, 98, 101, 102, 128, 133, 137, 153, 154, 158, 165 - 168, 170, 172, 180, 184 and 185 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 , 3, 4, 14, 17-18, 20-22, 25-26, 28, 32 and 52-56 of US Application 19/098,348 . Although the claims at issue are not identical, they are not patentably distinct from each other. The claims of the patent recite antibodies, nucleic acids , a method of making the antibody and methods of treatment comprising antibodies that comprise SEQ ID Nos as set forth in the claims, and the claims of the copending application recite methods of treatment comprising antibodies that comprise SEQ ID Nos with sequences 100% identical to sequences in the instant claims. Accordingly, the copending claims in many instances recite antibodies that anticipate the instant claims and the instantly claimed antibodies , nucleic acids and a method of making the antibody would have obvious to one of ordinary skill in the art because one would need to make the antibody using nucleic acids in order to practice the methods of the copending application. Therefore , one of skill in the art would consider the instant claims as an obvious variation of the copending claims , absent a showing otherwise . Conclusion No claims are allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Brad Duffy whose telephone number is 571-272-9935. The examiner can normally be reached FILLIN "Work schedule?" \* MERGEFORMAT Mon-Fri . If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu, can be reached on FILLIN "SPE Phone?" \* MERGEFORMAT 571-272-5205 . The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. Respectfully, Brad Duffy 571-272-9935 /Brad Duffy/ Primary Examiner, Art Unit 1643 February 27 , 2026