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.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 1/14/2026 has been entered.
Withdrawn Rejection
The rejection of claims 13, 20 and 22 under 103 is withdrawn in response to the amendments.
Priority
The present application was filed on 9/29/2021 and is a CON of PCT/EP2020/058266, filed 3/25/2020. Acknowledgment is also made of applicant's claim for foreign priority under 35 U.S.C. 119(a)-(d) to Application No. EP19166037.2, filed on 3/29/2019 in Europe.
Status of the Claims
Claims 13 and 20 and 22 are pending; claim 13 is amended, claims 1-12, 14-19 and 21 are canceled. Claims 13, 20 and 22 are examined below.
New Rejection
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 13, 20 and 22 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 a biosensor chip wherein the biosensor chip comprises the bispecific antibody bound to the immobilized heterodimeric fusion polypeptide.
The specification does not provide sufficient evidence that the claimed biosensor chip with the bispecific antibody bound to the immobilized heterodimeric fusion polypeptide is effective. The evidence provided merely shows sensograms obtained with an SPR biosensor chip that has initially no heterodimeric fusion polypeptide immobilized thereon. Afterwards, the heterodimeric fusion polypeptide is immobilized, then the bispecific antibody is introduced and binds to the heterodimeric fusion polypeptide to form a complex and then the complex dissociates and regenerates (see Figure 5 showing the SPR sensogram from initial baseline to immobilization/capture of the antigen via His tag, bispecific antibody injections, and finally to dissociation and regeneration, see also the specification page 39 lines 11-16 and page 49 lines 3-25). 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, namely using a biosensor chip that already contains the bispecific antibody bound to the heterodimeric fusion polypeptide immobilized thereon.
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 biosensor would function as intended (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, Creative Proteomics (retrieved online https://www.creative-proteomics.com/resource/overview-biacore-spr-technology.htm#:~:text=Sensorgram%20Analysis,also%20measured%20during%20this%20phase. Retrieved online on 3/30/2026) teaches that sensograms require a “Baseline Phase…before analyte is introduce…Association Phase…when the analyte binds…Dissociation Phase…after flow of analyte is stopped…release of the bound analyte” (page 3 para. 6).
Given the cited teachings of the prior art that biosensor chips require the analyte, i.e. the bispecific antibody, to not be bound to the immobilized heterodimer, the cited reference demonstrates that the use of the biosensor chip with the bispecific antibody bound to the immobilized heterodimeric fusion polypeptide is unpredictable. The function of the disclosed chip appears to be for the detection or analysis of the bispecific antibody binding to the polypeptide on the chip. If the bispecific antibody is already bound to the polypeptide on the chip, as now claimed, the chip cannot be used to contact analyte bispecific antibodies for their detection or analysis.
While the level of skill in the art is high, the amount of guidance provided regarding how to use the claimed biosensor is scant. Accordingly, the amount of experimentation required to determine how to use the recited biosensor is quite extensive.
Due to the large quantity of experimentation necessary to determine how to use the recited biosensor chip, 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 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.
New Rejection
Claims 13, 20 and 22 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.
Claim 13 and its dependent claims require a bispecific antibody that specifically binds to the first antigen and a second antigen of a heterodimeric fusion polypeptide, the heterodimeric fusion polypeptide comprising a first polypeptide (first antigen) fused to the N-terminus of a first antibody heavy chain Fc-region polypeptide of the IgG1 subtype, a second polypeptide (second antigen) fused to the N-terminus of a second antibody heavy chain Fc region polypeptide of the IgG1 subtype, the first and the second heavy chain Fc-region polypeptide form a disulfide-linked heterodimer, one or both of the heavy chain Fc-region polypeptides comprise a tag at its C-terminus for immobilization and the first and the second Fc-region polypeptide comprise the mutations T366W and T366S/L368A/Y407V, respectively.
The specification does not describe which amino acid residues, or other molecular components are present in the genus of bispecific antibodies encompassed by claims 13, 20 and 22. 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 generically the structure of antibodies is known, the structure of the presently recited antibodies can vary substantially within the above given claimed recitations. 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). The relevant antibody art confirms this quandary, indicating that “knowledge of an epitope or antigen used to generate a monoclonal antibody is insufficient for making the original antibody available, even if suitable in vitro test systems for screening are used.” See p. 8, lines 3-5 of WO 2009/033743 A1. Therefore, those of skill in the art would not accept that the inventor had been in possession of the full genus of antibodies and variants, fragments or derivates of the antibodies of the claims.
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).
Accordingly, Shaw et al. Nat Nanotechnol. 2019 February ; 14(2): 184–190. doi:10.1038/s41565-018-0336-3 (“Shaw”) teaches that different types of IgG bispecific antibodies have different flexibilities and avidities (“differences between the IgG subclasses, where IgG1 and IgG4 showed similar behaviour, while IgG2, which is the most rigid subclass, showed a “stepwise” behaviour, where the binding affinity was similar at short distances but became significantly stronger at around 14-16 nm. In contrast, IgG3, which is the most flexible subclass, showed strong binding at shorter distances and even more so at 14-16 nm” page 4 para. 2, see Figure 2).
See also, Jendroszek et al. Scientific Reports volume 11, Article number: 12663 (2021) https://doi.org/10.1038/s41598-021-92280-2 teaches that “[f]ollowing the initial association, the other Fab moiety can bind in an intra-molecular reaction called ring-closing (Fig. 1B). Ring-closing occurs intra-molecularly and is thus independent of the concentration. Instead, it depends on the structure of the antibody and antigen, which together define an effective concentration. Dissociation from a bivalent target requires simultaneous release of both Fab moieties, and thus depends on the ring-closing equilibrium and the effective concentration” (page 1 para. 3).
Shui et al. Mol. Cancer. 2025 Aug 4;24:212. doi: 10.1186/s12943-025-02390-y teaches that “[f]ull-length BsAbs with Fc regions exhibit longer half-lives, higher solubility, and increased stability due to their larger size and the neonatal Fc receptor” (page 3 col. 2 para. 2) and “Non-IgG-like BsAbs… For example, bispecific T cell engagers (BiTEs) are a distinct class of BsAbs, comprising… small size, improved tissue penetration, high flexibility, and high affinity connection between effector and target cells” (page 4 col. 1 para. 2).
Therefore, the art teaches that the structure of bispecific antibodies varies significantly and that the specific structure determines its capability to bind specifically to the first and second antigen.
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).
The skilled artisan cannot envision the detailed chemical structure of each genus of claimed bispecific antibodies. Conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of identification. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991). 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
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 13, 20 and 22 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.
Claim 13 recites the limitation "the first and the second antigen" in lines 5-6 and “the first antigen…the second antigen” in line 18. There is insufficient antecedent basis for this limitation in the claim. It is not clear which antigens “the first and the second antigen” or “the first antigen…the second antigen” refers to because “the first and the second antigen” or “the first antigen…the second antigen” can be interpreted in multiple ways. For example, they could be referring to the first and second polypeptide (lines 3-4) or to other two different antigens. Because of this a person having ordinary skill in the art would not be able to recognize the metes and bounds of the claim.
Similarly, claim 20 recites the limitation “the first antigen and the second antigen” in lines 1-2. There is insufficient antecedent basis for this limitation in the claim. It is not clear which antigens “the first antigen and the second antigen” refers to because “a first antigen and a second antigen” are not recited in claims 13 or 20.
Claim 20 also recites the limitation “the surface density of the heterodimeric fusion polypeptide” in lines 2-3. There is insufficient antecedent basis for this limitation in the claim. It is not clear to what surface density it is being referred to because a surface density of the heterodimeric fusion polypeptide immobilized on the sensor chip was not previously recited in claims 13 or 20.
Claim 22 is included in this rejection because it depends from rejected claim 13 but fails to clarify the scope of patent protection sought.
Response to Arguments
Applicant’s arguments with respect to claim(s) 13, 20 and 22 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FERNANDO IVICH whose telephone number is (703)756-5386. The examiner can normally be reached M-F 9:30-6:00 (E.T.).
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/Fernando Ivich/Examiner, Art Unit 1678
/CHRISTOPHER L CHIN/Primary Examiner, Art Unit 1677
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