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
The amendments filed on 8/21/2025 which claims 1, 5-18, and 21 were amended and claim 24 was newly added is acknowledged. Claims 3-4 and 22-23 were canceled.
Claims 1, 5-18, 20-21, and 24 are pending in the instant application.
Priority
This application is a 371 of PCT/EP2018/068856, filed on 7/11/2018 which claims priority to the foreign applications GB1717786.6 filed on 10/30/2017 and GB1711191.5 filed on 7/12/2017.
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 365(c) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
claim 11-13
The disclosure of the prior-filed applications, Application No. GB1711191.5 and GB1717786.6, fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. The R14A mutation of the HsTx1 peptide appears for the first time in application PCT/EP2018/068856, thus claims 11-13, have a priority date of 7/11/2018.
Withdrawn Rejections
The rejection of claims 1-8, 16, and 18-23 under § 112(b) is withdrawn in light of the amendments; the claim no longer recites the broad and narrow limitations of “comprising” and “consisting” in the same claim.
The rejection of claim 21 under § 112(b) is withdrawn in light of the amendments; this claim no longer expands the scope over the parent because the parent claim has now been broadened with the language of “comprising”.
The rejection of claims 1, 5, 8, 14, 16, and 20-21 under § 102(a)(1) is withdrawn in light of the amendments; the base claim 1 was limited to replacement of VL CDR2 which is not taught by Bazirgan.
The rejection of claims 1, 3-8, 11, 14, 16, 18, and 20-22 under § 103 is withdrawn in light of the amendments; the base claim 1 was limited to replacement of VL CDR2 which is not taught Bazirgan. The reference of Zhang teaches replacing the entire variable region, however the claims required the presence of an intact antibody VH domain. Thus the combination of references fails to teach the claimed structures.
Claim Rejections – 35 USC § 112(b)
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 24 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 24
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 24 recites the broad recitation “comprising”, and the claim also recites “consisting” which is the narrower statement of the range/limitation. More specifically, this claim is drawn to a “binding member comprising” a fusion protein comprising an RDS and a DDS; wherein the DDS “consist[s] of a peptide comprising no more than 10 amino acid substitutions or deletions relative to … SEQ ID NO: 370”. The quoted limitations are referred to in the simplified phrase “consisting of 0-10 mutations” throughout this office action. It is unclear how the “consists of” language modifies the DDS, given the there are no clear boundaries separating the DDS from the RDS, especially in light of being able to modify the non-cysteine residues of the DDS. One of skill in the art would not be able to determine if a given Knotbody infringed on a sequence consisting of a particular DDS versus a sequence “comprising a particular DDS, in the context of a peptide that comprises other amino acid sequences such as the RDS and partner domain, thus rendering this claim indefinite. The language “consisting of” cannot be meaningfully interpreted in this context. This claim is considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Dependent claims 2-8, 16, and 18-23 fail to cure these deficiencies, thus are also rendered indefinite.
Claim Rejections – 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
E, claim 1, 5-8, 11, 14, 16, 18, 20-21, and 24
Claims 1, 5-8, 11, 14, 16, 18, 20-21, and 24 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Claims 1, 5-8, 11, 14, 16, 18, 20-21, and 24 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for
replacing LCDR2 with a toxin peptide within the A07 and A12 antibody VL; and
the specific, functional Knotbodies of the anti-TACE antibody (D1A12) identified in Example 16;
it does not reasonably provide enablement for replacing any portion of LCDR2 with a KTX, ShK, or HsTx peptide in any given antibody, wherein the function of binding and inhibiting Kv1.3 is preserved. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Attention is directed to In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors: (1) the nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention:
A fusion protein comprising an antibody (or fragment thereof) and a toxin comprising 0-10 mutations (wherein the cysteine residues are preserved) of a HsTx peptide of SEQ ID NOs: 370-372, a ShK peptide of SEQ ID NO: 18, or a KTX peptide of SEQ ID NO: 14.
Breadth of claims:
The fusion protein can comprise any “binding member”, thus any antibody (or fragment thereof), and the toxin can replace any number of residues within LCDR2 with that binding member. The toxin must replace all or part of one of the antibody’s variable regions (e.g. LCDR2).
State of the prior art/Predictability or unpredictability of the art:
Proper folding of the antibody and the Knottin is also required for the fusion protein to be expressed in the first place. For example, Wang et al. (doi: 10.1073/pnas.1612803113) attempted the fusion of Moka1 (a Kv1.3 binding Knottin) into HCDR3 of the humanized antibody called Syn. Wang teaches that this fusion protein was poorly expressed due to problems with proper folding and general protein instability (pg 11502, col 1, para 3). Wang posited that LCDR3 and HCDR2 of the Syn antibody offer more solvent exposed loops amenable to fusing the Knottin, however, fusion into these locations also failed (pg 11502, col 1, para 3). Wang eventually achieved success when two residues of LCDR3 were replaced by Moka1 (pg 11502, col 1, para 4). Thus considerable experimentation is required to identify where and what specific residues in a given antibody could be substituted with a knottin, in order to generate the instantly claimed invention. Wang teaches that incorporating the knottin, Moka1, was successful in HCDR3 in the bovine antibody BVK (pg 11502, col 1, para 2), previously identified by Liu et al. (doi: /doi.org/10.1021/ja5130786) as being amenable to fusion. Wang also teaches that once they discovered that residues Gly92-Tyr93 in CDR3L of Syn could be replaced by Moka1 to generate a fusion protein that could bind and inhibit Kv1.3 (pg 11503, Table 1), they were also able to successfully swap Moka1 with another knottin, called Vm24, to generate another Kv1.3 inhibiting fusion protein (pg 11503, col 1, para 2). Thus, taken together, once a particular location on a given antibody has been successfully fused with a knottin, it is amenable to replacement with any other knottin. However, the identification of which residues of which antibody can be replaced can only be determined experimentally.
Example 16 of the instant specification describes a screen “To isolate functional knottin-antibody fusions, each of the knottin-antibody linker phage display libraries A to G, described above, were subject to two rounds of phage display selection with biotinylated trypsin as described in Example 3.” (pg 130, para 3). Only after this screening and selection process did applicant arrive at a collection of functional Knotbodies “Screening of clones picked from the unselected knottin linker antibody libraries C, E and G gave 0%, 1 % and 32% positive clones respectively indicating that a limited proportion of library members are capable of displaying a functional knottin donor. The hit-rates of clones obtained after phage display selection and monoclonal phage ELISA for libraries A, B, C, D, E, F and G was 11 %, 17%, 28%, 4%, 74%, 24% and 93% respectively, demonstrated an enrichment for KnotBodies that display a functional knottin.” (pg 131, para 1). Thus by applicant’s own admission, functional Knotbodies of the D1A12 antibody were not 100% successful, and required screening in order to identify which species of this group possessed the Knottin and possessed the binding properties/functionality of a Knotbody.
Amount of guidance/Existence of working examples:
In examples 1 and 2, applicant describes constructing a library of antibodies wherein LCDR1 and LCDR2 are replaced by Ecballium elaterium trypsin inhibitor-II (EETI-II), a plant-derived knottin that inhibits trypsin. In example 3, applicant describes a process wherein said library of generated EETI-II-antibody fusion proteins are screened for their ability to inhibit trypsin or not, demonstrating that not all fusion protein constructs generated possess the function of binding to its target. Example 4 describes another round of screening, wherein the EETI-II-antibody fusion proteins identified previously in example 3 as capable of inhibiting trypsin, were then paired with a human IgG1 heavy chain, and re-tested to confirm the knottin structure was preserved and still capable of inhibiting trypsin. Again demonstrating the lack of predictability of the preservation of the function of binding to its target. Example 7 describes swapping the EETI-II knottin, with a Kv1.3 blocking knottin, using the antibody VL’s, KB_A07 and KB_A12, that were previously demonstrated to be amenable to EETI-II knottin fusion at LCDR2 (as described in instant example 3). Example 11 describes generating variants of the KB_A07 and KB_A12 VL domains that include variable linkers to the fused knottin. In this example, applicant demonstrates that long, flexible linkers can result in the knottin failing to bind its target (pg 120, para 3). Thus applicant has provided two antibody VL frameworks amenable to fusion at a single position after considerable experimentation, followed by further optimization of the linker length.
Quantity of experimentation:
Given the difficulty of identifying what residues in which antibodies could be replaced by a knottin to generate a functional fusion protein that is folded properly and able to inhibit Kv1.3, one of skill in the art would have to undertake considerable experimentation in order to identify what particular residues in LCDR2 in which particular antibodies could be fused with a knottin wherein the function of binding Kv1.3 is preserved. Thus, a person of skill in the art, in undertaking the experimentation necessary to determine which residues of LCDR2 in a given antibody could be replaced by a knottin, would have no reasonable expectation that the majority of substitutions claimed would generate properly folded and successful Kv1.3 blocking fusion proteins. Applicant’s own specification corroborates the findings of Wang that screening needs to be performed in order to identify functional variants of the instantly claimed invention.
See the decision in Rasmusson v. SmithKline 413 F.3d 1318, 1325 (Fed. Cir. 2005) which stated: “Thus, at the end of the day, the specification, even read in the light of the knowledge of those skilled in the art, does no more than state a hypothesis and propose testing to determine the accuracy of that hypothesis. That is not sufficient. [Citation omitted.] ‘If mere plausibility were the test for enablement under §112, applicants could obtain patent rights to “inventions” consisting of little more than respectable guesses as to the likelihood of their success. When one of the guesses later proved true, the “inventor” would be rewarded the spoils instead of the party who demonstrated that the method actually worked.’”
Therefore, in view of the Wands factors as discussed above, e.g., the amount of guidance provided and the predictability of the art, to practice the full scope of the claimed invention commensurate in scope claimed herein, a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
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.
16/066638
Claims 1, 5-8, 11, 14-18, 20-21, and 24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 54, 63, 64, 86, 88, 92, 94, 100-103, 107, 112, 115, 128-136, and 138-147 of copending Application No. 16/066638 in view of Bazirgan et al. (US20160159928), Hoorick et al. (WO2015193452), Sullivan et al. (WO 2006116156), Zhang et al. (doi: 10.1002/anie.201603052), and Murphy et al. (WO2012104581).
This is a provisional nonstatutory double patenting rejection.
claim 1, 24
Regarding instant claims 1 and 24, the reference claims a fusion protein comprising a DDS inserted into the RDS (claim 54), wherein the DDS is a ShK or KTX (a.k.a. Kaliotoxin) peptide comprising zero mutations (claim 102), and the RDS is an antibody variable domain (claim 54). The reference claims the N terminal and the C terminal of the DDS are linked to the RDS with a linker of 0-4 amino acids in length (claim 54). The reference claims replacing all or part of any CDR region (claim 54). The reference claims the RDS is an antibody VL domain and the partner domain is a VH domain (claim 64). The reference claims the DDS replaces CDR2 of the antibody VL domain (claim 94). The reference claims replacing all or part of VL CDR2 of the RDS with the DDS (claim 153).
claim 5
Regarding instant claim 5, the reference claims the native N and C terminals of the DDS are linked to the RDS domain (claim 103).
claim 6
Regarding instant claim 6, the reference teaches artificial N and C terminals being generated by the cyclization and linearization of the DDS domain (claim 107).
claim 7
Regarding instant claim 7, the reference does not teach an IC50 of less than 10-9 M via whole cell patch clamp assay.
Hoorick teaches an immunoglobulin that binds Kv1.3 with an IC50 of 10-9 M or lower (claim 2) as determined by Patch Clamp Assay (claim 1). Note that 10-9 M is equivocal to 1 nM. Hoorick teaches the Patch Clamp Assay utilized whole cells (pg 124, para 1). Hoorick teaches the immunoglobulin inhibits Kv1.3 activity (claim 3).
It would have been obvious to combine the teachings of the reference and Hoorick, because Hoorick teaches that whole-cell patch clamp assays are effective in measuring potassium influx or efflux and that an IC50 of less than 10-9 M is desirable for immunoglobulins that inhibit Kv1.3 channel activity, and the reference teaches a fusion protein contains a peptide that inhibits Kv1.3 activity. One of skill in the art would have had a reasonable expectation of success because Hoorick teaches whole cell patch clamp assays are effective for measuring Kv1.3 channel activity and that an IC50 of less than 10-9 M is a desirable target.
claim 8
Regarding instant claim 8, the reference does not teach using a HsTx peptide as the DDS.
Bazirgan teaches CDR3 can be replaced with an HsTx1 peptide (pg 3, para 0030; claim 23; SEQ ID NO: 600).
It would have been obvious to combine the teachings of the reference and Bazirgan teaches that HsTx1 peptides inhibit Kv1.3 activity and the reference teaches a fusion protein also designed to inhibit Kv1.3 activity. One of skill in the art would have had a reasonable expectation of success because Bazirgan teaches that HsTx1 peptides can inhibit Kv1.3 activity.
claim 11
Regarding instant claim 11, the reference does not teach using an HsTx peptide as the DDS.
Sullivan teaches the modified R14A HsTx1 peptide of instant SEQ ID NO: 395 (SEQ ID NO: 281), shown below.
instant_395 ASCRTPKDCADPCAKETGCPYGKCMNRKCKCNRC 34
Sullivan_281 ASCRTPKDCADPCAKETGCPYGKCMNRKCKCNRC 34
**********************************
Sullivan teaches the HsTx1 peptide analogue as being a part of a fusion protein (claim 36), wherein the HsTx1 peptide, represented by X2, replaces the entire variable region of the VH (Fig 1A). Sullivan teaches the fusion proteins of the invention are useful for treatment of diabetes, obesity, rheumatoid arthritis, (abstract) and inflammation (pg 188, example 46).
It would have been obvious to combine the teachings of the reference and Sullivan, because both Bazirgan and Sullivan are both teaching fusion proteins comprising a Kv1.3 inhibiting peptide and a portion of an immunoglobulin for the purpose of treating inflammation mediated by the Kv1.3 channel. One of skill in the art would have had a reasonable expectation of success because Sullivan teaches the HsTx1-R14A peptide is also effective at inhibiting Kv1.3 activity in order to reduce inflammation.
claim 14
Regarding instant claim 14, the reference claims the DDS being a ShK peptide (claim 102). The reference does not specify the sequence of the ShK peptide in the claims.
Zhang teaches fusing the Kv1.3 targeting ShK peptide to a human IgG1 Fc fragment in order to extend the in vivo half-life relative to the isolated ShK peptide (pg 9308, col 2, para 2). Zhang teaches generating a library of Fc-ShK variants, and screening for those that retained Kv1.3 binding ability (pg 9308, col 2, para 2). Zhang teaches ShK peptide has a sequence comprising 100% sequence identity to instant SEQ ID NO: 18 (SI Figure 4).
It would have been obvious to combine the reference and Zhang because the reference teaches using the ShK peptide and Zhang identifies the peptide as being the sequence, RSCIDTIPKSRCTAFQCKHSMKYRLSFCRKTCGTC. One of skill in the art would have had a reasonable expectation of success of using the known ShK sequence disclosed by Zhang in the fusion protein of the reference because the sequence described by Zhang is the same as the one disclosed in the reference and Zhang successfully incorporated that sequence into an antibody-ShK fusion protein.
claim 15
Regarding instant claim 15, the reference claims the RDS and linkers of the fusion proteins sequences of Table 1 comprising EETI-II knottin peptides (claim 146). The reference teaches the framework regions surrounding the EETI-II knottin is: DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAAGV…SRSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGASPPYTFGQGTKVEIKR (entry CDR2_E_08, SEQ ID NO: 136). The reference also claims the peptide can be a ShK peptide (claim 102).
Zhang teaches ShK peptide has a sequence comprising 100% sequence identity to instant SEQ ID NO: 18 (SI Figure 4), which is RSCIDTIPKSRCTAFQCKHSMKYRLSFCRKTCGTC.
It would have been obvious to combine the reference with Zhang to swap out the knottin in one of the sequences in Table 1, with the ShK peptide disclosed by Zhang, arriving at instant SEQ ID NO: 31, as shown below.
ref_136 DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAAGV------- 53
Zhang_ShK -----------------------------------------------------RSCIDTI 7
instant_31 DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAAGVRSCIDTI 60
ref_136 ----------------------------SRSGVPSRFSGSGSGTDFTLTISSLQPEDFAT 85
Zhang_ShK PKSRCTAFQCKHSMKYRLSFCRKTCGTC-------------------------------- 35
instant_31 PKSRCTAFQCKHSMKYRLSFCRKTCGTCSRSGVPSRFSGSGSGTDFTLTISSLQPEDFAT 120
ref_136 YYCQQGASPPYTFGQGTKVEIKR 108
Zhang_ShK ----------------------- 35
instant_31 YYCQQGASPPYTFGQGTKVEIKR 143
One of skill in the art would have had a reasonable expectation of success because the reference claims a ShK peptide can be incorporated into an antibody and gives several example framework regions that are amenable to knottin insertion and Zhang provided the sequence of the ShK peptide to be inserted.
claim 16, 21
Regarding instant claims 16 and 21, the reference claims the DDS being a KTX peptide (a.k.a. Kaliotoxin, claim 102), which teaches instant SEQ ID NO: 14 within reference SEQ ID NO: 33).
claim 17
Regarding instant claim 17, the reference claims the binding member comprising instant SEQ ID NO: 33 (reference SEQ ID NO: 33).
claim 18
Regarding instant claim 18, the reference does not teach the partner domain comprising instant SEQ ID NO: 30.
Bazirgan teaches that the modified VH can comprise part of a bispecific antibody or multispecific antibody (pg 28, para 0293), wherein the partner domain is represented by one of the other antigen binding domains.
Murphy teaches a method of treating a TACE-mediated condition comprising administering anti-TACE antibodies to a patient in need thereof (pg 4, para 2-3), wherein the TACE mediated condition is an immune related disorder, rheumatoid arthritis, inflammation, or cancer (pg 4, para 4). Murphy teaches an anti-TACE antibody that comprises instant SEQ ID NO: 30 (SEQ ID NO: 15), shown below.
instant_30 -------------------EVQLVESGGGLVRPGGSLRLSCAASGFTFSSYAMSWVRQAP 41
Murphy_15 MDWTWRVFCLLAVAPGAHSEVQLVESGGGLVRPGGSLRLSCAASGFTFSSYAMSWVRQAP 60
*****************************************
instant_30 GKGLEWVSAISGSGGSTYYADSVKGRFTISRDNTKNSLYLQMTSLRADDTAFYYCVKDFG 101
Murphy_15 GKGLEWVSAISGSGGSTYYADSVKGRFTISRDNTKNSLYLQMTSLRADDTAFYYCVKDFG 120
************************************************************
instant_30 PGYGTGWFDYWGPGTLVTVS---------------------------------------- 122
Murphy_15 PGYGTGWFDYWGPGTLVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTV 180
********************
Murphy teaches that the anti-TACE antibody can comprise a portion of a bispecific antibody (claim 20).
It would have been obvious to combine the teachings of the reference, Bazirgan, and Murphy because (1) Bazirgan teaches their ShK-antibody fusion protein can be combined with other antibody binding domains and (2) Murphy teaches that their anti-TACE antibody can be combined with other antibody binding domains as part of a bispecific antibody, and (3) the reference provides a working ShK-antibody fusion protein. One of skill in the art would have had a reasonable expectation of success because the references all teach that their engineered binding proteins are effective in treating inflammation and cancer, thus combining two elements known to treat the same condition is considered obvious.
claim 20
Regarding instant claim 20, to avoid improperly treating what is disclosed in a reference patent or copending application as if it were prior art in the context of a nonstatutory double patenting analysis, the examiner must first properly construe the scope of the reference claims. The portion of the specification of the reference that describes subject matter that falls within the scope of a reference claim may be relied upon to properly construe the scope of that claim. In particular, when ascertaining the scope of the reference’s claim(s) to a compound, the examiner should consider the reference’s specification, including all of the compound’s uses that are disclosed. See Sun Pharm. Indus., 611 F.3d at 1386-88, 95 USPQ2d at 1801-02. See MPEP § 804(B)(1).
The specification of the copending application describes a method of treating an individual having a disease or condition involving an ion channel disfunction, such as an autoimmune disease or pain, using the fusion protein described (pg 54, para 2-5; pg 72, para 2) or in the treatment of neurological disorders such as Alzheimer’s disease (pg 81, para 4).
Pertinent Prior Art
Insertion of a knottin to replace all or part of LCDR2 in claim 23 was not found in the prior art. However, replacement of CDR2-like structures within the human CD4 protein with the scorpion-derived knottins have been performed as discussed in Vita et al. 1998 (doi: 10.1002/(SICI)1097-0282(1998)47:1<93::AID-BIP10>3.0.CO;2-H). Human CD4 is not an antibody, thus lacks the structures of an antibody such as a VH and VL domain described in base claim 1 and 24. The incorporation of a knottin into CD4 was generated in order to develop a model system for studying HIV interactions with CD4, as opposed to blocking potassium channel signaling in those with autoimmune disorders. There is no teaching in Vita that would motivate one to insert a knottin into an antibody. Note: while this limitation of claim 1 and 24 was not found in the prior art, it fails to meet the scope of enablement requirement. See 112(a) rejection above for further details.
Allowable Subject Matter
The instant specification is enabled for the fusion of a Kv1.3 binding knottin at LCDR2 within the A07 and A12 VL sequences. The excised LCDR2 is denoted using ellipses (…), below. LCDR1 and LCDR3 have been underlined below.
>A07
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAAGV...SRSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGASPPYTFGQGTKVEIKR
>A12
QSVLTQPPSVSEAPRQRVTITCSGSSSNIGNNAVNWYQQLPGKAPKLLIYAAGR...ANSGVSDRFSAAKSGTSASLAINGLRSEDEADYYCAAWDDSLNGYVFGTGTKLTVLG
There is no teaching in the prior art that these VL domains could accommodate a fused knottin wherein the function of binding and inhibiting Kv1.3 is preserved. As described in the 112(a) rejection above, knottin insertion into an antibody is a highly unpredictable process. There is no universal antibody locus that one can insert a knottin into, nor is there any single antibody which is able to accommodate a knottin at any position. To express a functional knottin, each knottin insertion position in each antibody must be found empirically, and then verified if the knottin is folded correctly and maintains its ion-channel blocking function.
claim 9, 10, 12, 13, 15, 17
Regarding claims 9, 10, 12, 13, 15, and 17, the Knottin-antibody fusions represented by instant SEQ ID NOs: 389 (claim 10), 395 (claim 13), 31, 32 (claim 15), and 33 (claim 17) were not found in the prior art. The nucleotide sequences encoding the KnotBodies of instant SEQ ID NOs: 381 (claim 9) and 382 (claim 12) were also not found in the prior art, nor were their corresponding amino acid sequences.
The closest prior art to the A12 framework of the Knottin-antibody fusion described by instant SEQ ID NOs: 389 and 395 is that of Brentjens et al. (WO2016090327, SEQ ID NO: 73) shown below, with the CDR regions underlined and the HsTx1-R14A peptide in bold.
instant_395 QSVLTQPPSVSEAPRQRVTITCSGSSSNIGNNAVNWYQQLPGKAPKLLIYAAGRASCRTP 60
Brentjens_73 QPVLTQPPSVSEAPRQRVTISCSGSSSNIGNNAVNWYQQLPGKAPKLLIYFDD------- 53
* ******************:***************************** .
instant_395 KDCADPCAKETGCPYGKCMNRKCKCNRCANSGVSDRFSAAKSGTSASLAINGLRSEDEAD 120
Brentjens_73 ---------------------------LLSSGVSDRFSGSKSGTSASLAISGLQSEDEAD 86
.********.:**********.**:******
instant_395 YYCAAWDDSLNGYVFGTGTKLTVLG----------------------------------- 145
Brentjens_73 YYCAAWDDSLNGYVFGTGTKVTVLGSRGGGGSGGGGSGGGGSLEMAQVQLQQSGPGLVKP 146
********************:****
Brentjens does not teach inserting a knottin into this VL which targets BCMA. It is understood that successful fusion of a knottin into an antibody is an unpredictable process (as discussed in the 112(a) enablement rejection), thus there was no guidance to arrive at the specific VL insertion cites within the A07 and A12 VL regions, given the art of record.
Response to Arguments
Applicant’s arguments filed on 16/629877 have been fully considered but they are not persuasive.
112(a); pg 7, para 7
Applicant argues that a person of skill in the art could have performed the screen to identify what linkers length is optimal, thus their claims to any linker length are enabled. Applicant argues the application of Rasmusson v. SmithKline 413 F.3d 1318, 1325 (Fed. Cir. 2005) is improper.
The enablement rejection is based on the location of the knottin insertion within the antibody, not based on the linker length. The instant specification recites the following study was conducted after linker-length was optimized “The hit-rates of clones obtained after phage display selection and monoclonal phage ELISA for libraries A, B, C, D, E, F and G was 11 %, 17%, 28%, 4%, 74%, 24% and 93% respectively, demonstrated an enrichment for KnotBodies that display a functional knottin.” (pg 131, para 1). Thus by applicant’s own admission, functional Knotbodies of the D1A12 antibody were not 100% successful, and required screening in order to identify which species of this group possessed the Knottin and possessed the binding properties/functionality of a Knotbody. After performing three rounds of screening, applicant identified two antibody VL frameworks that were amenable to replacement. The optimization of the linker length was secondary to this effort. The findings of Rasmusson are still considered relevant because Applicant is relying on a person of skill in the art to find which species of their claimed genus actually possess the claimed function.
112(a); pg 9, para 4
Applicant argues that the supplied Declaration provides evidence that a person of ordinary skill in the art is capable of identifying working species of the genus claimed, thus the claimed genus is enabled.
Examiner finds that the declaration bullet point 6 confirms the unpredictability by stating 82 of 87 screened antibodies exhibited activity against Kv1.3. However, that is only the hit rate of Library F, whereas library A had a hit rate of only 11% (pg 131, para 1). Bullet point 7 of the declaration states that it takes a single worker less than 6 months to perform the experimentation necessary to perform the screen to identify functional Knotbodies from the non-functional Knotbodies. There are no defined guidelines for what is considered undue length of effort. Examiner will merely state that six months of work on a single task appears substantial. More presciently, at issue is the fact that experimentation is required in order to identify the functional members of the claimed genus. MPEP 2164.01(a) states “The test of enablement is whether one reasonably skilled in the art could make or use the invention from the disclosures in the patent coupled with information known in the art without undue experimentation.”). A patent need not teach, and preferably omits, what is well known in the art.” However, in the instant case, it is not known which antibodies, and at what positions, can accommodate a knottin successfully. Otherwise such screening processes to verify the function of each candidate would not be necessary. The details of the instant application are analogous to the findings in In Amgen Inc. v. Sanofi, Aventisub LLC, 987 F.3d 1080 (Fed. Cir. 2021), where the Supreme Court confirmed that if each individual candidate must be screened for its function, then there is a lack of enablement: “the court relied on evidence showing that the scope of the claims encompassed millions of antibodies and that it was necessary to screen each candidate antibody in order to determine whether it met the functional limitations of the claim. Id. at 1088. Consequently, the Federal Circuit concluded that there was a lack of enablement.” In order to satisfy the enablement requirement, Applicant must describe the invention sufficiently so that a screen is not required to identify the functional members of the instantly claimed genus.
NSDP; pg 11, para 3
Applicant requests that the double patenting rejection over U.S. Application No. 16/066638 be held in abeyance.
A request to hold a rejection in abeyance is not a proper response to a rejection. Rather, a request to hold a matter in abeyance may only be made in response to an OBJECTION or REQUIREMENTS AS TO FORM (see 37 CFR 1.111(b) and MPEP §714.02). Thus, the double patenting rejections of record have been maintained as no response to these rejections has been filled by applicant at this time.
Conclusion
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.
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/L.A.E./
Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675