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 .
Priority
The examiner acknowledges the provisional application filed on 04 August 2022. The effective filing date is 04 August 2022.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 07 March 2024 and 18 March 2025 are being considered by the examiner.
Status of Application, Amendments, and/or Claims
Claims 1-97 are the original claims filed on 04 August 2023. In the preliminary amendment of 05 December 2023, claims 16-38, 59-92, and 95-97 are cancelled, and claims 3-15, 41-43, 56-58, 93, and 94 are amended. Claims 1-15, 39-58, 93, and 94 are pending and the subject of this office action.
Drawings
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Specifically, the applicant refers to colored figures in the descriptions of figures 5 and 6. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Claim Rejections - 35 USC § 112
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, 5-15, 39-58, 93, and 94 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.
Regarding claims 1, 5-15, 39, and 44, the claims reference antibodies or fragments thereof that are comprised of variable heavy and light chains that share at least about 90% sequence identity with SEQ ID Nos: 1-4 (heavy) and SEQ ID Nos: 5-10 (light). The applicants use of the term “about” creates a degree of uncertainty regarding the bounds of the limitations established within the claims. The specification provides guidance to the interpretation of the term “about”, in regard to a measurable value, such as amount of polypeptide, dose, time, temperature, enzymatic activity, or other biological activity (page 30 lines 18-21). It states that the term “about” is meant to encompass variations of ±20%, ±10%, ±5%, ±1%, ±0.5%, or even ±0.1% of the specified amount. However, it is unclear if this applies to % sequence identity. If one was to apply the largest defined variation encompassed by the definition to the claims, then the term “at least about 90% identical” could be interpreted as 90% ± 18%. In this case, the relevant prior art search space would broaden. When applying the definition, mentioned above, multiple BDAC2 antibodies, disclosed in the prior art, could be used for prior art rejections. One such example is disclosed in US20160280790, in which BDAC2 antibodies comprised of heavy and light variable regions, SEQ ID NO:6 and SEQ ID NO:8, respectively, share 91.5% and 83.7% sequence identity, respectively, with their counterparts from the instant application, SEQ ID NO: 1 and SEQ ID NO:5 (alignments shown below).
Reference SEQ ID NO:6 EVKLVESGGGLVKPGGSLKLSCAASGFTFSTMSWVRQTPEKRLEWVASISSGGSTYYPDS 60 91.5
Instant SEQ ID NO:1 EVQLVESGGGLVKPGGSLRLSCAASGFTFSTMSWVRQAPGKRLEWVASISSGGSTYYPDS 60
**:***************:******************:* ********************
Reference SEQ ID NO:6 VKGRFTISRDNARNILYLQMSSLRSEDTAMYYCARPSYDGYSSWFAYWGQGTLVTVSA 118
Instant SEQ ID NO:1 VKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARPSYDGYSSWFAYWGQGTLVTVSS 118
************:* *****.***:****:***************************:
Reference SEQ ID NO:8 DIVLTQSPASLAVSLGQRATISCKASQSVDYDGDGFMNWYQQKPGQPPKLLIYTASNLES 60
Instant SEQ ID NO:5 EIVLTQSPATLSLSPGERATLSCKASQSVDYDGDGFMNWYQQKPGQAPRLLIYTASNLES 60
:********:*::* *:***:************************* *:***********
Reference SEQ ID NO:8 GIPARFSGSGSGTDFTLNIHPVEEEDAATYYCQQSNEDPWTFGGGTKLEIK 111
Instant SEQ ID NO:5 GVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSNEDPWTFGGGTKVEIK 111
*:***************.* :* ** *.******************:***
Claims 40-43, 45-58, 93, and 94 are rejected under 35 USC 112(b) by virtue of their dependency on a rejected claim.
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.
WRITTEN DESCRIPTION
Claims 1-15, 39-58, 93, and 94 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 claims contain 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.
Claims 1-15, 39-58, 93, and 94 are drawn to antibodies, wherein the heavy chain variable regions are comprised of one of the sequences described by SEQ ID NO: 1-4, and wherein the light chain variable regions are comprised of one of the sequences described by SEQ ID NO: 5-10. The sequence modifications, differentiating each heavy and light chain sequence, are the result of engineered mutations aimed at lowering undesired post translational modification within the CDRs (page 115). However, the scope of the claims is broadened, by allowing up to about 10% variability (≤ 90% identity) in the both regions. The current application provides a limited number of light chain and heavy chain pairings comprising the sequences referred to in SEQ ID Nos: 1-10, Table 3 of the specification, but provides no examples of antibodies varying from the referenced sequences.
The state of the art around the effective filing date of the claimed invention also does not provide an adequate number of species of the claimed genus or the necessary structure-function correlation. Rather, the art demonstrates that antibody functionality is known to depend on the entire antibody structure, particularly a full complement of six CDRs. Chiu ML, et al. (2019) Antibody Structure and Function: The Basis for Engineering Therapeutics. Antibodies (Basel). Dec 3;8(4):55 (herein Chiu) teaches that the antigen-binding site of immunoglobulins is formed by the pairing of the variable domains (VH and VL) of the Fab region. Chiu teaches that each domain contributes three complementarity determining regions (CDRs), specifically, three from the VL and three from the VH, and that the six CDR loops are in proximity to each other resulting from the orientation of the VL and VH regions. The configuration of the VL and VH brings the three CDRs of the VL and VH domains together to form the antigen-binding site (page 4, paragraph 2). Here, Chiu teaches that the interaction between the heavy and light chain variable domains effects the conformation of the binding region of the antibody and therefore the antibody’s ability to bind to its target. In essence, the teachings of Chiu point out that the binding site is formed by the combination of the heavy and light chain CDRs (six regions) together.
Rabia L, et al. (2018) Understanding and overcoming tradeoffs between antibody affinity, specificity, stability, and solubility. Biochem Eng. J. 15(137); 365-374 (herein Rabia) discusses the challenges with optimizing antibody properties and states “the most important antibody properties relate to their natural functions, such as their high binding affinity and specificity mediated by their complementarity-determining regions (CDRs) within the variable regions... Other key natural antibody properties include their effector functions — such as antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC)- which are mediated by their constant regions” (page 2, paragraph 1). Rabia further teaches that “most antibodies identified during the initial discovery process are not suitable for therapeutic use and require additional optimization. For example, the binding affinities of some lead antibodies are not high enough for therapeutic applications” (page 2, paragraph 3). Rabia goes on to state that “natural antibody affinity maturation relies on the introduction of somatic mutations followed by clonal selection of antibody variants with improved affinity. However, not all somatic mutations contribute to antibody affinity...antibodies accumulate some somatic mutations to increase affinity and others to compensate for the destabilizing effects of affinity-enhancing mutations” (page 2, paragraph 4). Rabia further provides an example of researchers who introduced mutations throughout variable frameworks and CDRs and created libraries to sort antibody variants with high antigen binding. In this case an antibody was identified that displayed increased affinity but had a significant reduction in stability (page 3, paragraph 2). Rabia concludes by stating that “a final key area of future work is the development of improved computational methods for predicting mutations in antibody CDRs and frameworks that co-optimize multiple antibody properties” and that “future efforts will also need to improve structural predictions of antibody CDRs — especially the long and highly variable heavy chain CDR3-to accurately predict CDR mutations that are beneficial to different antibody properties” (page 9, paragraph 4 — page 10 paragraph 2).
The claims establishing the structure of the antibodies, claims 1, 5-15, 39, and 44, allow for 10% sequence variation, with no restrictions as to their location within the amino acid sequence, hence variations may occur within the CDRs of either chain. As taught by Chiu, the antigen-binding characteristics of antibodies are determined by the six CDRs of the heavy and light chains, and by modifying these regions the functional characteristics of the antibody are altered. The instant application does provide working examples, in which the CDRs are modified to limit post-translation modifications, but they are limited to a small number of antibodies comprising light chain and heavy chain pairings comprising the sequences referred to in SEQ ID Nos: 1-10, Table 3 of the specification, and are inadequate to represent the genus being claimed.
Furthermore, the guidance provided in the specification relating to modifications of the variable region amino acid sequences were in the context of limiting unwanted isomerization (pages 115-120). The guidance provided involves identifying potential sites of isomerization, generating multiple variants of the chain with the site modified, evaluating the performance of the resulting antibody (paired with an unmodified complementary chain), then testing multiple combinations of modified heavy and light chains. The guidance provided, essentially describes experimentation without any concrete structure-function relationship, beyond identifying sites of potential isomerization.
The prior art as summarized by Rabia, teaches that introducing mutations in antibody structure, particularly in the CDR regions, is not predictable and requires experimentation following mutation to ensure that binding affinity is maintained and a stable antibody is created. Rabia further spoke to the use of libraries and computational methods for predicting and co-optimizing antibody properties and demonstrated how these methods are not robust enough yet to yield predictable results.
Neither the specification or the prior art teaches a structure-function relationship that would allow for one skilled in the art to modify 10% of the variable region sequence, especially when including CDRs, with a predictable functional outcome. When combining this unpredictability with a lack of functional limitations, as in claims 1, 5-15, 93, and 94, the claims effectively describe antibodies with unknown structure and function. Claims 2, 39-58 and 93 do contain functional limitations, specificity towards BDCA2 (claims 39, 41-55, 57, 58, and 93) or BDCA2 specificity with affinity limitations (claims 2, 40, and 56). However, it is unclear how one would incorporate up to 10% sequence variation into the variable regions of the heavy and light chain, while maintaining the functional requirements.
Overall, it is not evident from the disclosure or the prior art that applicant was in possession of a representative number of species of the claimed genus, at the time of filing, required to provide an adequately defined structure-function relationship. Thus, there is insufficient support for the claimed 10% sequence variation within the variable regions the claimed antibodies. Therefore, the instant claims are found to not meet the written description requirement.
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.
ENABLEMENT
Claims 1, 3-15, 93, and 94 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 claims contain 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.
The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is “undue” include, but are not limited to: 1) nature of the invention, 2) state of the prior art, 3) relative skill of those in the art, 4) level of predictability in the art, 5) existence of working examples, 6) breadth of claims, 7) amount of direction or guidance by the inventor, and 8) quantity of experimentation needed to make or use the invention. In re Wands, 858 F.2d 731,737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
Regarding the nature of the invention, the invention describes antibodies that comprise variable heavy and light chain regions comprised of sequences selected from SEQ ID Nos: 1-4 (heavy) and SEQ ID Nos: 5-10 (light). The breadth of the claims extends beyond the antibodies disclosed by these sequences as 10% sequence variation is allowed anywhere within the disclosed variable regions.
As discussed for the 112(a) written description rejections for claims 1, 3-15, 93, and 94, the language of the claims, specifically those establishing the structure of the antibodies (claims 1, and 5-15), fail to define an antibody with a definite function. Since no function can be assigned to the antibodies claimed, it would be impossible to enable the antibodies for any use.
Conclusion
No claims allowed. The claims are free of prior art infringements, and would be allowable if the 112(b) and 112(a) rejections were to be overcome. In regard to the 112(b) rejections, amending the claims so as to remove the “about” term, would be sufficient to overcome the associated rejections. In regard to the 112(a) rejections, if the applicant was to amend the rejected claims so as to either remove the language permitting sequence variation or introduce language limiting the variation to prior art-supported framework positions, while maintaining 100% sequence identity in the CDRs, then the claims would be allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MATTHEW CURRAN METCALF whose telephone number is (571)272-5520. The examiner can normally be reached 7:30AM-5:00PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama, can be reached at (571)272-2911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MATTHEW CURRAN METCALF/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647