DETAILED ACTION
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 .
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.
Withdrawn Objections/Rejections
The objections to the claims are withdrawn in response to the amendments.
The rejection of the claims under 101 and 103 are withdrawn in response to the amendments.
Priority
Acknowledgment is made of the present application as a proper National Stage (371) entry of PCT Application No. PCT/US2020/037603, filed 6/12/2020, which claims benefit under 35 U.S.C. 119(e) to provisional application No. 62/861,003, filed 06/13/2019.
Status of the Claims
Claims 1, 3-10 and 12-22 are pending; claims 1, 3-4, 6, 10, 12-13, 15, 18-20 and 22 are amended, claims 2 and 11 are canceled; claims 4, 13 and 19-22 are withdrawn. Claims 1, 3, 5-10, 12 and 14-18 are examined below.
Maintained Rejections
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 3, 5-10, 12 and 14-18 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. This is a written description rejection.
The claims recite “one or more additional scFvs reactive with one or more oligomeric beta amyloid disease variants, TDP-43 disease variants, alpha-syn disease variants, or tau disease variants,… wherein the one or more additional scFvs reactive with one or more oligomeric beta amyloid disease variants, TDP-43 disease variants, alpha-syn disease variants, or tau disease variants has a light chain CDR and heavy chain CDR combination or a light chain CDR combination and truncated heavy chain selected from the group consisting of: SEQ ID NOS: 21…24…41…61…64…and 83…; SEQ ID NOS: 21…24…41…101…103…83…; SEQ ID NOS: 21…25…42…61…65…84…; SEQ ID NOS: 21…26…43…62…66…85…; SEQ ID NOS: 21…26…43…101…104…85…; SEQ ID NOS: 21…27…44…61…67…86…; SEQ ID NOS: 21…27…44…101…105…86…; SEQ ID NOS: 21…28…45…61…68…87…; SEQ ID NOS: 21…28…45…101…106…87…; SEQ ID NOS: 22…29…46…61…69…88…; SEQ ID NOS: 22…29…46…101…107…88…; SEQ ID NOS: 23…30…47…63…70…89…; SEQ ID NOS: 23…30…47…102…108…89…; SEQ ID NOS: 21…32…49…; SEQ ID NOS: 21…27…50…61…72…91…; SEQ ID NOS: 21…26…51…61…73…92…; SEQ ID NOS: 21…26…51…101…110…92…; SEQ ID NOS: 21…33…52…61…74…; SEQ ID NOS: 21…33…52…101…111…; SEQ ID NOS: 21…34…53…61…75…93…; SEQ ID NOS: 21…34…53…101…112…93…; SEQ ID NOS: 21…35…54…61…76…94…; SEQ ID NOS: 21…35…54…101…113…94…; SEQ ID NOS: 21…36…55…61…77…95… and…SEQ ID NOS: 21…36…55…101…114…95…”.
However, the specification does not describe which amino acid residues are present in the genus of scFvs encompasses by the claims. Furthermore, the specification fails to disclose the structures common to all members of the genus and fails to provide sufficient specific examples of agents to be used. In the absence of a known or disclosed correlation between structure and function, claims which encompass variants defined by their function are generally not considered described. Applicant is directed to MPEP § 2163 for guidelines on compliance with the written description requirement.
Regarding the claimed scope that includes antibodies, the Federal Circuit has clarified Written Description as it applies to antibodies in the recent decision Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017). The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. 112(a) (or pre-AIA first paragraph) requires adequate written description of the antibody itself. Amgen, 872 F.3d at 1378-79. The Amgen court expressly stated that the so-called “newly characterized antigen” test, which had been based on an example in USPTO-issued training materials and was noted in dicta in several earlier Federal Circuit decisions, should not be used in determining whether there is adequate written description under 35 U.S.C. 112(a) for a claim drawn to an antibody. Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the “newly characterized antigen” test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad, 598 F.3d 1336, 1345 (Fed. Cir. 2010). In view of the Amgen decision, adequate written description of an antigen alone is not considered adequate written description of a claimed antibody to that antigen, even when preparation of such an antibody is routine and conventional. Id.
While the specification discloses in Table 3 (pages 18-20) examples of amino acid sequence modifications to specific CDR regions of 15 scFvs, i.e. the claimed SEQ ID NOS: 1-15, these are not sufficient to encompass the claimed scope of one or more additional scFvs reactive with one or more oligomeric beta amyloid disease variants, TDP-43 disease variants or tau disease variants. The structure of the presently recited antibodies can vary substantially within the above given claimed recitations. Although the claims limit the CDR of the one or more additional scFvs to a combination, the claims do not limit each scFv to its corresponding CDRs as disclosed in Table 3. Therefore, the claim encompasses combinations of scFvs that are not properly disclosed, which raises concerns under 112a written description. A person having ordinary skill in the art would question whether Applicant was in possession of the genus of antibodies encompassed by the claim. As noted in Amgen, knowledge that an antibody binds to a particular epitope on an antigen tells one nothing at all about the structure of the antibody, wherein “instead of analogizing the antibody-antigen relationship to a ‘key in a lock,’ it [is] more apt to analogize it to a lock and ‘a ring with a million keys on it.” (Internal citations omitted). Therefore, those of skill in the art would not accept that the inventor had been in possession of the full genus of scFvs reactive with one or more oligomeric beta amyloid disease variants, TDP-43 disease variants or tau disease variants.
Functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. Abbvie Deutschland GMBH & Co. v. Janssen Biotech, Inc. (759 F.3d 1285 (Fed. Cir. 2014). “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." Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005).
Consequently, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the full genus of antibodies encompassed by the claims. Further, given the well-known high level of polymorphism of immunoglobulins and antibodies, the skilled artisan would not have recognized that applicant was in possession of the vast repertoire of encompassed antibodies.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111 (Fed. Cir. 1991), clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117). The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
Therefore, the instant claims do not meet the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph.
New Rejection
Claims 1, 3, 5-10, 12 and 14-18 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. This is an enablement rejection.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. The specification does not reasonably provide enablement for diagnosing/monitoring a subject with frontotemporal dementia (FTD) using an scFv reactive with TDP-43 disease variants having a combination of light chain CDRs and heavy chain CDRs of SEQ ID NOS: 21, 31, 48, 61, 71, 90; or SEQ ID NOS: 21, 31, 48, 101, 109, 90.
The specification does not provide sufficient evidence that the claimed method of using the scFv is effective for diagnosing or monitoring FTD, or even that the scFv is reactive with TDP-43 disease variants. The evidence provided shows “little to no AD-TDP1 reactive variant…in all three sample groups (Fig. 1A)” (specification para. 160, see Fig. 1A). Therefore, 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.
MPEP § 2164.01 states:
The standard for determining whether the specification meets the enablement
requirement was cast in the Supreme Court decision of Minerals Separation Ltd. v. Hyde, 242 U.S.261, 270 (1916) which postured the question: is the experimentation needed to practice the invention undue or unreasonable? That standard is still the one to be applied.
In re Wands, 858F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). Accordingly, even though the statute does not use the term "undue experimentation," it has been interpreted to require that the claimed invention be enabled so that any person skilled in the art can make and use the invention without undue experimentation.
In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404 (Fed. Cir. 1988).
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." These factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
In regard to Wands factors (A) and (B), the breadth of the claims needed to enable the invention is determined by whether the scope of enablement provided to one skilled in the art by the disclosure is commensurate with the scope of protection sought in the claims. AK Steel Corp. v. Sollac, 344 F.3d 1234, 1244, 68 USPQ2d 1280, 1287 (Fed. Cir. 2003); In re Moore, 439 F.2d 1232, 1236, 169 USPQ 236, 239 (CCPA 1971). The propriety of a rejection based upon the scope of a claim relative to the scope of the enablement concerns (1) how broad the claim is with respect to the disclosure and (2) whether one skilled in the art could make and use the entire scope of the claimed invention without undue experimentation.
The nature of the invention is a biological/chemical case, where there is natural unpredictability in performance of certain species other than those specifically enumerated; see MPEP § 2163. Accordingly, it is the Office’s position that undue experimentation would be required to practice the claimed method(s), with a reasonable expectation of success, because it would not have been predictable from the disclosure that the claimed scFv would function as claimed with respect to reacting with TDP-43 disease variants for diagnosing/monitoring FTD (see MPEP § 2164.03).
In regard to Wands factors (C), (D) and (E), the state of the prior art is what one skilled in the art would have known, at the time the application was filed, about the subject matter to which the claimed invention pertains and provides evidence for the degree of predictability in the art; see MPEP § 2164.05(a).
Accordingly, Acharya et al. F1000Research 2017, 6:851 Last updated: 14 AUG 2017 doi: 10.12688/f1000research.11774.1 (“Acharya”) teaches that “[w]henever possible choose an antibody that is recommended by the vendor for your species and application…. If you must use an antibody for non-recommended applications, be prepared to rigorously validate the antibody and to optimize vendor-suggested protocols for your specific experimental conditions” (page 4 bridging paragraph of cols. 1-2).
Given the cited teachings above that undue experimentation is required when using an antibody that is not recommended, and given that the specification admits that the claimed scFv, had “little to no AD-TDP1 reactive variant…in all three sample groups (Fig. 1A)” (specification para. 160, see Fig. 1A)), the use of the claimed scFv is unpredictable.
While the level of skill in the art is high, the amount of guidance provided regarding how to use the claimed scFv in the claimed methods is scant. Accordingly, the amount of experimentation required to determine how to use the recited scFv to diagnose or monitor FTD as claimed is quite extensive.
Due to the large quantity of experimentation necessary to determine how to use the recited scFv to react with TDP-43 variants and diagnose/monitor FTD, the lack of direction/guidance presented in the specification regarding the same, the absence of working examples directed to the same, the complex nature of the invention, the limited state of the prior art, the unpredictability of the effects of complex biological molecules on diseased physiological systems, and the breadth of the claims, undue experimentation would be required of the skilled artisan to make and/or use the claimed invention.
In view of all of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention, and thus, the claimed invention does not satisfy the requirements of 35 U.S.C. §112 first paragraph.
Maintained Rejections
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 1, 3, 5-10, 12 and 14-18 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.
The term “disease variants” is unclear throughout the claims. The specification discloses a broad definition of “variants”, i.e. “[v]ariants: sequences derived by deletion (so-called truncation) or addition of one or more amino acids to the N-terminal and/or C-terminal end, …; deletion or addition of one or more amino acids/nucleic acids at one or more sites in the sequence; or substitution of one or more amino acids/nucleic acids at one or more sites in the sequence” (para. 66). Notably the definition of “variants” from paragraph 66 of the specification is directed to protein variants not disease variant. Therefore, it is not clear what is meant by “disease variants” (emphasis added). The specification fails to define the term “disease variant” The term “disease variant” can be interpreted in multiple ways. For example, a “TDP-43 disease variant” may be interpreted as a disease that is associated with TDP-43, i.e. a disease variant of a TDP-43-related disease. Furthermore, the term “TDP-43 disease variant” may also be interpreted as a protein variant of TDP-43 associated with a disease. Due to these two different possible interpretations of the term “disease variants” the claims are indefinite. A person having ordinary skill in the art would not be able to recognize the metes and bounds of the claim.
The claims further recite “diagnosing a subject…detecting binding between the one or more scFvs and the biological sample” (claim 1), “the detection of binding between the…scFvs…to the biological sample is indicative that the subject has or is likely to develop FTD” (claim 1), “monitoring a subject…detecting binding between the one or more scFvs and the first biological sample” (claim 10), “detecting binding between the one or more scFvs and the second biological sample” (claim 18). However, it is not clear how detecting binding between the scFvs and the biological sample would relate to FTD. Notably detecting binding between the one or more scFvs and the biological sample is not the same as detecting binding between the one or more scFvs and the one or more oligomeric beta amyloid variants, TDP-43 variants or tau variants. Because of this, a person having ordinary skill in the art would question the metes and bounds of the claim.
For these reasons the claims are indefinite.
Response to Arguments
Applicant's arguments filed 6/1/2026 have been fully considered but they are not persuasive.
Regarding the 112a written description rejections,
Applicant argues that “ As amended, independent claims 1, 10, and 19 do not claim a functionally defined antibody genus. Instead, they explicitly recite defined combinations of light-chain and heavy chain CDR sequences by SEQ ID NO…Each scFv is structurally defined by a specific CDR combination expressly disclosed in Table 3…Accordingly, a person of ordinary skill in the art would readily recognize from the specification that Applicant was in possession of scFvs having the exact CDR sequences and combinations now recited in claims 1 and 10 at the time of filing” (page 14 paras. 2-3).
However, as explained in detail above, although the claims limit the CDR of the one or more additional scFvs to a combination, the claims do not limit each of the one or more additional scFv to its corresponding CDR combination as disclosed in Table 3 (see 112a written description rejection above). Therefore, the claims do encompasses combinations of scFvs that are not properly disclosed. Thus, the claims remain rejected under 112a written description.
Regarding the 112b indefiniteness rejections,
Applicant argues that “Applicant amended the claims to clarify that the variants are disease variants. One skilled in the art would understand disease variant to mean protein variant biomarkers in frontotemporal dementia (FTD)” (page 15 para. 2).
However, the term “disease variants” is unclear (see 112b rejection above). In short, the term can be interpreted in multiple ways; e.g., as variants of a disease or as variants of a protein associated with a disease. Therefore, Applicant’s argument is not persuasive.
Applicant further argues that “According to the Office Action, "it is not clear how detecting binding between the one or more scFvs and the biological sample would relate to FTD." Id at 10. As discussed above, the scFvs are specific for detecting disease variants in FTD. Thus, a person having ordinary skill in the art would understand that detecting binding between the one or more specific scFvs and the biological sample is indicative that the subject has or is likely to develop FTD” (page 15 para. 3).
However, given that it is not clear what is meant by “disease variants” (see rejection above), contrary to Applicant’s remark, a person having ordinary skill in the art would not understand that detecting binding between the one or more specific scFvs and the biological sample is indicative that the subject has or is likely to develop FTD (see rejection above). The claims remain rejected under 112b.
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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/Fernando Ivich/Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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