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 .
Claims 1-13 have been canceled.
Claims 14-29 are pending in the instant application.
Applicant’s election without traverse of the invention of group I, drawn to antibodies that bind the BK virus in the reply filed on July 29, 2026 is acknowledged.
Claims 21-25 and 27-29 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on July 29, 2026.
Claims 14-20 and 26 are under examination in this office action.
Information Disclosure Statement
The IDS form received 11/21/2024 is acknowledged and the references cited therein have been considered.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 14, 16, 18-20 and 26 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Applicant has broadly claimed antibodies or antigen binding fragments thereof which have the functional property of binding the BK virus. Such antibodies are recited as comprising various amounts of specific structure, such as sets of full length VH and VL domains recited by SEQ ID number in dependent claim 17, sets of six fully defined CDR sequences as recited in dependent claim 15, and antibodies comprising mutations to CDRs recited by SEQ ID number as set forth in independent claim 14. To support such claims, the instant specification discloses the 336F07 clone and two variants thereof, namely 336F07-var1 and 336F07-var4 in Table 4. Notably, data concerning how the mutants were generated and identified (such as a working example of a CDR mutagenesis screening assay) do not appear to be disclosed in the specification.
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 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 KLRG1) 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. and Winkler et al., see entire documents). 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 the VP1 protein of the BK virus) 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 has claimed antibodies that bind the BK virus with varying levels of structural specificity recited by SEQ ID number. Notably, independent claim 14 sets forth 3 genera of antibody species in (i), (ii), and (iii) which recite six CDR sequences identified by SEQ ID number. However, in addition to the exact sequences recited by SEQ ID number, the claim also recites variants of said SEQ ID numbers which comprise one or two substitution mutations. Thus the claim encompasses antibodies wherein all 6 CDR sequences are fully defined and known to bind BK as per the data of the instant application, as well as variants comprising from 1 to 12 total CDR mutations, at random locations in the CDRs (apart from any one CDR having no more than two mutations) and substitutions to random residues. It should be noted that the SEQ ID numbers recited in part (i) of claim 14 are those of the 336F07 clone, while (ii) recites those of the 336F07-var1, and part (iii) recites the CDRs of 336F07-var4, and that CDR the alterations in the variants are very minimal, with var1 having only a single T to K change at residue 16 of the heavy chain CDR2 as compared to 336F07 while the only alteration present in var4 is a single N to S mutation at position 4 of the light chain CDR3 relative to 336F07. Thus, the claims encompass explicitly altering the very structure which gives rise to the function of antigen binding and recite significantly more variability than that which was demonstrated by applicant to be present in antibodies that have the recited functional properties including binding various BK virus serotypes while not cross-reacting with the JC virus (see for example claim 18). It is well known that many amino acid side chains strongly alter the secondary structure of a polypeptide, such as prolines forming bends or kinks in a polypeptide backbone while cystines often form intra- and intermolecular disulfide bonds (Stryer, see entire document). Given that changes as small as a single residue change can abrogate antigen binding as taught by Rudikoff et al. and Winkler et al. it appears unreasonable that the amount of specific structure positively recited in independent claim 14 is sufficient as up to 12 random mutations can be present, two in each CDR, and the two disclosed variants are not reflective of the amount of claimed sequence diversity. Additionally, claim 19 recites an antibody product that competes for binding to the BK virus with the antibody of independent claim 14. Thus, the antibody product of claim 19 is not structurally limited in any way as it need not contain any amount of sequence identity with the antibody of claim 14 so long as it has the recited functional properties of “competing” for binding, and note that no definition or guidance for how much the presence of one antibody disrupts the binding of another antibody must be present in order to meet the threshold of “competing” for binding. As such, claim 19 recites complexly functional claiming of the antibody product.
Thus, while artisans would reasonably accept that applicant was in possession of antibodies comprising six fully defined CDR sequences identified by SEQ ID number that have the functional properties of binding the VP1 polypeptide of the BK virus at the time of filing, artisans would not reasonably accept that applicant was in possession of the breadth of antibody mutants and competitors as presently recited.
Claims 14, 16, 18-20 and 26 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.
Applicant has claims anti-BK virus antibodies or antigen binding fragments thereof which are required to comprise various amounts of specific biological sequence defined by recited SEQ ID numbers. The instant specification discloses the 336F07 antibody clone and two variants thereof named 336F07-var1 and 336F07-var4, but data from mutagenesis studies showing how the named variants were identified does not appear to be disclosed.
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).
The instant claimed antibodies are required to comprise various amounts of biological sequence via the recited SEQ ID numbers. Specifically, in independent claim 14 complete CDR sequences are recited as well as “variants” of said SEQ ID numbers which comprise up to 2 random substitution mutation per CDR (so potentially 12 total mutations relative to the CDRs of the named reference antibodies disclosed by the instant specification). While antibodies can be made via standard hybridoma techniques wherein an animal, such as a mouse is vaccinated with the target antigen (in the instant case the BK virus or its VP1 polypeptide) such techniques do not allow artisans any control over the biological sequences recovered from such protocols. Given that the claims do require the presence of at least some portion of specific sequences, the only reasonable way to make such antibodies is via the techniques of recombinant antibody production, and such techniques typically minimally require six fully defined CDR sequences to ensure antigen binding activity in the resultant antibody (see for example Kipriyanov et al.). The instant claims fail to provide the artisans with this level of information that reasonably is needed to make that which is claimed for all embodiments, namely an antibody that binds the BK virus. It should be noted that claim 16 depends from claim 14, but since the CDR sequences of claim 14 are not fixed, the percent identity limitations concerning VH and VL domains in claim 16 are not limited to just framework mutations but encompass CDR mutations as well. It is well known that many amino acid side chains strongly alter the secondary structure of a polypeptide, such as prolines forming bends or kinks in a polypeptide backbone while cystines often form intra- and intermolecular disulfide bonds (Stryer, see entire document), and given that as discussed above even a single mutation in a CDR can abrogate binding, making an antibody wherein the all the CDRs can comprise random mutations isn’t reasonably expected to maintain binding to anything at all as all six collectively are needed for binding as per the Janeway textbook.
Therefore, in view of the breadth of the claims, the teachings of the art, and the guidance and direction of the instant specification, artisans would be unable to make the full breadth of the instant claimed bispecific antibodies without first engaging in additional unpredictable basic science research and experimentation.
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.
Claims 16 and 18 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 applications subject to pre-AIA 35 U.S.C. 112, 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) 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 16 recites the broad recitation “at least about 85%” which really is the range 85-100, and the claim also recites multiple subranges with at least 99% sequence identity (i.e. 99-100) which is the narrowest statement of the range/limitation. The claim(s) are 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. More concretely, if the prior art teaches a sequence 92% identical, which fits in some ranges but is excluded from others, is the claim anticipated? If yes because it satisfies the broadest range the narrower subranges should be removed as they do not serve to limit the claim, and if no, then why are the broad ranges recited at all as they are not limiting? This issue of nested ranges also appears in claim 18 with “less than about X nM” recitations which are really the range 0-X nM. Recitation of just the largest range, as well as moving subranges to separate dependent claims are potential solutions.
Additionally, regarding claim 18, the phrase "for example" (actually recited as “(e.g., 2, 3, 4, 5, 6, 7, 8 or 9)” as well as “e.g., as described in Example 2”) renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Removal of the phrases is strongly suggested
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.
Claim 19 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Abend et al. (WO 2017/046676).
Abend et al. disclose the P8D11 antibody (see entire document). This antibody binds the BK virus and thus “competes” for binding with the antibody of independent claim 14. See also figure 2 of the instant application. Note that the antibody claimed in claim 19 need not have any amino acid residue in common with that of the antibody claimed in claim 14, as all that is required is the functional property of “competition” which in the absence of an explicit definition of guidance in the specification simply means that it binds the same antigen. Given that P8D11 binds BK virus that condition has been met. Amending the claim to require the claimed antibody to have specific biological sequences, such as for all six CDRs, is the most obvious means to overcome this rejection, and other means are undoubtedly possible.
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.
Claim 19 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 11,919,943. Although the claims at issue are not identical, they are not patentably distinct from each other because the issued claims anticipate that which is presently claimed.
The issued claims read upon the 319C07 antibody as disclosed in the instant specification, an unsurprising fact as the application which became the ‘943 patent is the parent of the instant application. Instant claim 19 claims an antibody that “competes with” the antibody of instant claim 14, while instant claim 14 recites the 336F07 clone and sequence variants thereof. Importantly, the actual antibody claimed in instant claim 19 need not have any amount of sequence identity with the antibody of claim 14 as the language in claim 19 is 100% functional in nature. The instant specification discloses that 319C07 and 336F07 bind the same or highly similar epitopes on the VP1 polypeptide of the BK virus. Given that the issued claims are limited in structure via the requirement to comprise specific SEQ ID numbers while the antibody of instant claim 19 has no structural limitations whatsoever, the issued claims necessarily anticipate that which is presently claimed. Cancelation of instant claim 19 is suggested.
Claim Objections
Claims 15 and 17 are objected to as being dependent upon a rejected independent claim, but would be allowable if rewritten in independent form including all of the limitations of the independent claim and any intervening claims.
No claims are allowable.
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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Michael Szperka
Primary Examiner
Art Unit 1641
/MICHAEL SZPERKA/Primary Examiner, Art Unit 1641
Prosecution Insights