DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s response and amendments received July 13, 2026 are acknowledged.
Claims 8, 9, 18, 20-34, 39 have been canceled.
Claims 1, 2, 5, 15, 16, 19, 35, and 40 have been amended.
Claims 41 has been added.
Claims 1-7, 10-17, 19, 35-38, 40, and 41 are pending in the instant application.
Claims 1-7, 10-17, 19, 35-38, 40, and 41 are under examination in this office action.
Claim Rejections - 35 USC § 102
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 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.
The rejection of claim 40 under 35 U.S.C. 102(a)(1) as being anticipated by Andrien et al. (US 9,079,949) has been withdrawn in view of applicant’s claim amendment which change the category of invention to be a method of treating human HSCT-TMA as compared to the previously presented antibody kit product, and the recited treatment protocol is not disclosed or an obvious variant of dosing information disclosed by Andrien et al.
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.
The rejection of claim 40 on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 9,079,949 has been withdrawn in view of applicant’s claim amendments which change the category of invention from product to method and the issued claims do not teach the instant claimed treatment methods.
The rejection of claim 40 on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 9,371,377 has been withdrawn in view of applicant’s claim amendments which change the category of invention from product to method and the issued claims do not teach the instant claimed treatment methods.
The rejection of claim 40 on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 9,663,574 has been withdrawn in view of applicant’s claim amendments which change the category of invention from product to method and the issued claims do not teach the instant claimed treatment methods.
The rejection of claim 40 on the ground of nonstatutory double patenting as being unpatentable over claims 1-36 of U.S. Patent No. 9,206,251 in view of Andrien et al. (US 9,079,949) has been withdrawn in view of applicant’s claim amendments which change the category of invention from product to method and the issued claims do not teach the instant claimed treatment methods.
The rejection of claim 40 on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 12,459,992 in view of Andrien et al. (US 9,079,949) has been withdrawn in view of applicant’s claim amendments which change the category of invention from product to method and the issued claims do not teach the instant claimed treatment methods.
The rejection of claim 40 on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of U.S. Patent No. 10,227,400 in view of Andrien et al. (US 9,079,949) has been withdrawn in view of applicant’s claim amendments which change the category of invention from product to method and the issued claims do not teach the instant claimed treatment methods.
The rejection of claim 40 on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of U.S. Patent No. 9,803,007 in view of Andrien et al. (US 9,079,949) has been withdrawn in view of applicant’s claim amendments which change the category of invention from product to method and the issued claims do not teach the instant claimed treatment methods.
The rejection of claim 40 on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 9,107,861 in view of Andrien et al. (US 9,079,949) has been withdrawn in view of applicant’s claim amendments which change the category of invention from product to method and the issued claims do not teach the instant claimed treatment methods.
The rejection of claim 40 on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 11,434,280 in view of Andrien et al. (US 9,079,949) has been withdrawn in view of applicant’s claim amendments which change the category of invention from product to method and the issued claims do not teach the instant claimed treatment methods.
The following are new grounds of rejection necessitated by applicant’s claim amendments received July 13, 2026
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.
Claim 41 is 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 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.
Applicant has broadly claimed methods of treating human HSCT-TMA by administering a genus of anti-C5 antibodies partially defined by SEQ ID number via a detailed dosing protocol. The recited genus of antibodies binds C5, is effective at treating HSCT-TMA at the recited drug masses and timing intervals, and has a heavy chain polypeptide “at least 90% identical” to SEQ ID NO:14 and a light chain polypeptide which is “at least 90% identical” to SEQ ID NO:11. It should be pointed out that SEQ ID NOs:11 and 14 are full length light and heavy antibody claims respectively and do not comprise any Xaa or otherwise variable residues, and that these sequences are the same as the antibody commercially sold as ravulizumab/ULTOMIRIS. To support such a genus, the specification discloses working examples wherein ravulizumab was administered to patients, and no working examples concerning antibody mutagenesis appear to be disclosed.
The guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, § 1 "Written Description" Requirement make clear that if a claimed genus does not show actual reduction to practice for a representative number of species, then the Requirement may be alternatively met by reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the genus. See MPEP 2163. In The Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412) 19 F. 3d 1559, the court held that disclosure of a single member of a genus (rat insulin) did not provide adequate written support for the claimed genus (all mammalian insulins). In this same case, the court also noted: “A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. See Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). It is only a definition of a useful result rather than a definition of what achieves that result. Many such genes may achieve that result. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin [e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate."). Accordingly, naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.” The court has further stated that “Adequate written description requires a precise definition, such as by structure, formula, chemical name or physical properties, not a mere wish or plan for obtaining the claimed chemical invention.” Id. at 1566, 43 USPQ2d at 1404 (quoting Fiers, 984 F.2d at 1171, 25 USPQ2d at 1606). Also see Enzo-Biochem v. Gen-Probe 01-1230 (CAFC 2002). Recent court cases have emphasized the need for correlation between a well-defined structure and recited functional limitations. For example, the courts have indicated that recitation of an antibody which has specific functional properties in the absence of knowledge of the antibody sequences that give rise to said functional properties do not satisfy the requirements for written description. See for example AbbVie Deutschland GmbH v. Janssen Biotech. Inc. 759 F.3d 1285 (Fed. Cir. 2014). Such cases have indicated that that it is improper to allow patentees to claim antibodies by describing something that is not the invention, i.e. the antigen, as knowledge of the chemical structure of an antigen does not provide information as to what an antibody binding that antigen necessarily looks like (i.e. the primary amino acid structure of the antibody). Applicant is reminded that the courts have long ruled that “Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features.” See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895. As such, disclosure of a screening assay to test for functional properties of an antibody (such as its ability to bind C5) does not provide evidence of possession of the antibody itself. Further, courts have long ruled that “When a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus.” See Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005). Also, “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.” See AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69.
It should be pointed out that it is well established in the art that the formation of an intact antigen-binding site requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three different complementarity determining regions, CDR1, 2 and 3, which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin (Janeway et al., see entire selection). It is also known that single amino acid changes in a CDR can abrogate the antigen binding function of an antibody (Rudikoff et al., see entire document, particularly the abstract and the middle of the left column of page 1982 as well as Winkler et al.). Thus, based upon the prior art, skilled artisans would reasonably understand that it is the structure of the CDRs within an antibody which gives rise to the functional property of antigen binding, the epitope to which said CDRs bind is an inherent property which appears to necessarily be present due to conservation of critical structural elements, namely the CDR sequences themselves.
Artisans are well aware that knowledge of a given antigen (for instance human C5) provides no information concerning the sequence/structure of antibodies that bind the given antigen. For example, Edwards et al. teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences spanning almost the entire heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lambda and V-kappa light chain germlines, and with extensive diversity in the HCDR3 region sequences (that are generated by VDJ germline segment recombination) as well, see entire document). Similarly, Lloyd et al. teach that a large majority of VH/VL germline gene segments are used in the antibody response to an antigen, even when the antibodies were selected by antigen binding, as their sequencing studies revealed that out of 841 unselected and 5,044 selected antibodies, all but one of the 49 functional VH gene segments was observed (see entire document). Goel et al. disclose the synthesis of three mAbs that bind to the same short (12-mer) peptide and found that the sequences of these antibodies which bound the same epitope exhibited diverse V gene usage indicating their independent germline origin (see entire document). Further, it should be noted that degenerate binding of the same structural motif by antibodies does not require the existence of sequence homology or identity at any of their CDRs or other chemical similarities at the antigen-binding sites; side chain mobility of epitope residues can confer steric and electrostatic complementarity to differently shaped combining sites, allowing functional mimicry to occur (Lescar et al., see entire document, in particular Abstract and Discussion). As such, it does not seem possible to predict the sequence/structure of an antibody that binds a given antigen as there does not appear to be any common or core structure present within all antibodies that gives rise to the function of antigen binding. Further, given data such as that of Edwards et al. indicating the diversity of sequence bound in a population of antibodies that bind to a given antigen, no number of species appears to reasonably representative of the breadth of the genus of antibodies that bind the given antigen. Indeed, Kanyavuz et al. teach that “Theoretically, under physiological conditions, the human immune system can generate BCRs with 1026 distinct sequences, an astronomical number that is far greater than the calculated number of all B cell clones that can be generated during the lifespan of a healthy human (estimated to be 4 × 1014).
As discussed above, applicant’s working examples all administered ravulizumab and no working examples, guidance, and/or direction concerning how the structure of ravulizumab can be altered while maintaining functional properties including binding the C5 antigen. The polypeptide of SEQ ID NO:11 is 214 residues, so sequences 90% or more identical can have up to 21 mutations, while the 448 residues of SEQ ID NO:14 allows for 44 mutations while meeting the limitation of “at least 90% identical”. Claim 41 places no restrictions upon where mutations can be located relative to SEQ ID NOs:11 and 14, and thus the claims allow doe a large amount of mutations within the CDRs, which as discussed above are the very structures generally accepted in the art as giving rise to the function of antigen binding. Given that as evidenced by for example Rudikoff et al. and Winkler et al., changes as small as a single CDR residue can abrogate binding, such blanket percent identity are not reasonably correlated with maintaining antibody functions such as antigen bindings as the CDRs which provide the structure upon which antigen binding depends are not excluded from mutation by the instant claimed methods.
Therefore, in view of the breadth of the claim artisans would reasonably conclude that while applicant was in possession of the methods wherein ravulizumab was administered, applicant was not in possession of the full breadth of antibodies comprising heavy and light chains at least 90% identical to ravulizumab (i.e. SEQ ID NOs:14 and 11 respectively) as presently recited at the time the instant application was filed. Amendment of the claims to minimally require that the administered anti-C5 antibodies comprise the six unmutated CDR sequences of ravulizumab is one possible approach to obviating the issues discussed above.
Claim 41 is 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 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.
Applicant has claimed methods of administering a genus of antibodies that bind C5. The antibodies administered as part of the methods of treating HSCT-TMA are recited as comprising antibody heavy and light chains that are “at least 90% identical” to SEQ ID NOs:14 and 11 respectively. Notably, the recited SEQ ID numbers are the full length antibody sequences of the commercially available anti-C5 antibody ravulizumab/ULTOMIRIS. While disclosed working examples administer ravulizumab, examples concerning mutagenesis, particularly CDR mutagenesis of ravulizumab does not appear to be disclosed. Given that SEQ ID NO: 14 is 448 residues, “at least 90% identical” allows for 44 mutations while the 214 residues of SEQ ID NO:11 allows for 21 mutations. Further, such mutations can be located anywhere within the recited sequence as per the present claim language.
It is well known in the art that the formation of an intact antigen-binding site requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three different complementarity determining regions, CDR1, 2 and 3, which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin (Janeway et al., see entire selection). It is also known that single amino acid changes in a CDR can abrogate the antigen binding function of an antibody (Rudikoff et al., and Winkler et al., see entire documents). In the instant independent claim, the claimed antibodies are required to comprise biological sequences recited as being “at least” 90% identical to reference sequences, and thus the only reasonable way to make such reagents is using the tools of molecular biology and recombinant antibody production. However, concordant with the teachings of Janeway et al., such recombinant production typically requires six CDR sequences for conventional structure antibodies (Kipriyanov et al., see entire document). As has already been discussed above, claim 41 allows for the mutations relative to the ravulizumab reference sequences to be located anywhere, including the CDRs themselves. Given the total number of mutations that can be present, 2 or more whole CDR sequences can be completely randomized as in general a CDR is on the order of about 10 residues or so. Given that CDR alterations as small as a single CDR can abrogate antigen binding activity as shown by Rudikoff et al. and Winkler et al., it does not appear reasonable that such a large amount of random sequence will maintain antigen binding activity, and no working examples concerning antibody mutagenesis that still confers C5 binding activity appear to be disclosed. Therefore artisans cannot reasonably make the antibodies as presently claimed in the absence of extensive unpredictable basic science research and experimentation, and if the full genus of antibodies cannot be made the claimed administration method cannot be practiced.
Double Patenting
Claims 1-7, 10-17, 19, 35-38, 40, and 41 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-51 of copending Application No. 19/108,880. Although the claims at issue are not identical, they are not patentably distinct from each other because the copending claims anticipate that which is claimed.
Specifically the copending claims recite methods of administering anti-C5 antibodies that have the CDR sequences of ravulizumab as well as ravulizumab itself at drug masses, time intervals, and patient weights that are the same as those presently recited (compare instant and copending claim 1s) as well as encompassing patient populations of low weight (i.e. less than 20 kg) that were excluded from the instant claims as per the amendments of 7/13/2026. The copending claims also recite supplemental dosing instructions for patients who are given RBC transfusions as part of their therapy. Kits for use in practicing the copending method claims are also recited (see for example copending claims 47 and 49-51). Thus the copending claims recite more limitations, and thus are narrower in scope than what is presently claimed.
It should be noted that the ‘880 application has a 371 filing date of 3/5/2025 which is after the mailing date of the prior office action in the instant application.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
No claims are allowable.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Michael Szperka whose telephone number is (571)272-2934. The examiner can normally be reached Monday-Friday 8:30-5:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached at 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Michael Szperka
Primary Examiner
Art Unit 1641
/MICHAEL SZPERKA/Primary Examiner, Art Unit 1641
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