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 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.
Priority
The instant application, filed 08/09/2023, is a 371 filing of PCT/CN2022/075502, filed 02/08/2022, and claims foreign priority to CN202110178859.1, filed 02/09/2021.
Status of Claims/Application
Applicant’s preliminary amendment filed on 08/09/2023 is acknowledged. Claims 1-12 and 14-18 are amended; claim 13 is cancelled; and claims 19-21 are new. Claims 1-12 and 14-21 are currently pending and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 08/09/2023 and 03/10/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
Nucleotide and/or Amino Acid Sequence Disclosures
Claim 1 recites amino acid sequences for HCDRs 1-3 and LCDRs 1-3 comprising four or more defined amino acids without an accompanying SEQ ID NO.
The instant specification is missing the Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1). See item 1) a) or 1) b) below.
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specification Objection
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The following embedded hyperlinks were identified in the specification. Prefixes and non-top level domain browser-executable code are bolded for clarity.
Page 63, line 4: http://www.ncbi.nlm.nih.gov/projects/igblast/;
Page 63, line 8: http://www.imgt.org/IMGT_vquest and http://www.ncbi.nlm.nih.gov/igblast/;
Page 68, line 10: http://www.ncbi.nlm.nih.gov/igblast/
Claim Objections
Claim 18 is objected to because of the following informalities: as amended, lines 2-3 of the claim recite “the antibody or the antigen-binding fragment thereof according to claim 1, a detection composition comprising the antibody or the antigen-binding fragment thereof”. It appears that the limitation is missing an “or” between “claim 1” and “a detection composition” Appropriate clarification/correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 5 and 16 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 5 recites the limitation “such as IgG1, IgG2, IgG3 or IgG4, preferably IgG1 subtype or IgG4 subtype”. The use of the phrases "such as" and “preferably” renders the claim indefinite because it is unclear whether the limitations following the phrases are part of the claimed invention or exemplary embodiments. See MPEP § 2173.05(d).
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 5 recites the broad recitation any IgG subtype, and the claim also recites “such as IgG1, IgG2, IgG3 or IgG4, preferably IgG1 subtype or IgG4 subtype” which is the narrower 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.
Appropriate correction is required.
Claim 16 recites the limitation "the drug combination according to claim 1" in line 2. There is insufficient antecedent basis for this limitation in the claim. Claim 1 is drawn to an antibody or antigen binding fragment thereof, and does not recite a drug combination.
Appropriate correction is required.
In the instant office action, the claim is interpreted as being dependent on claim 15, which does recite a drug combination.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 2 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 1 is drawn to an antibody or antigen binding fragment and recites HCDR1-3 and LCDR1-3 sequences required in the antibody. Claim 2 depends on claim 1 and recites heavy and light chain variable regions of the antibody or antigen binding fragment. In claim 2, the heavy and light chain variable regions claimed do not all contain the CDRs required in claim 1.
For instance, claim 1 requires that HCDR1 be SYHMS; however, at least the following heavy chain variable regions recited in claim 2 do not comprise this required sequence: SEQ ID NOs: 85 (in part I), 87 (in part II), 91 (in part IV), 93 (in part V), 95 (in part VI), 97 (in part VII), 101 (in part IX), 105 (in part XI), 107 (in part XII), 111 (in part XIV), 113 (in part XV), and 142 (in part XXI).
As the variable light and heavy chain variable regions recited in claim 2 do not include all of the CDRs required in claim 1, claim 2 does not include all of the limitations of the claim upon which it depends.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Scope of Enablement
Claim 16 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating cancer, does not reasonably provide enablement for preventing cancer. 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.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue,’ not 'experimentation.'" (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case are discussed below.
The nature of the invention
Claim 16 is drawn to a method of preventing and/or treating the recited cancers, comprising administering a drug combination. As discussed above in the rejection under 112(b), the claim is interpreted in the instant office action as depending on claim 15, which recites that the drug combination comprises the antibody or antigen binding fragment thereof of claim 1 in combination with one or more therapeutic agent is selected from the recited antibodies.
The breadth of the claims
The claim is broad in that encompasses prevention of the recited cancers.
The specification does not define “preventing”. In absence of a limiting definition by the applicants, “preventing” is interpreted as defined according to IIME as provided in Wojtczak, A. (2002) Glossary of Medical Education Terms Medical Teacher 24(4): 357; 1-25. IIME defines “prevention” as promoting health, preserving health, and to restore health when it is impaired, and to minimize suffering and distress (page 16, “Prevention”). IIME states that “primary prevention refers to the protection of health by personal and community wide effects, such as preserving good nutritional status, physical fitness, and emotional well-being, immunizing against infectious diseases, and making the environment safe.” IIME states that “secondary prevention can be defined as the measures available to individuals and populations for the early detection and prompt and effective intervention to correct departures from good health”. IIME further states that tertiary prevention consists of the measures available to reduce or eliminate long-term impairments and disabilities, minimize suffering caused by existing departures from good health”.
Thus, in its broadest reasonable interpretation, the prevention of a condition suggests that that the onset of the condition never occurs and the patient’s health is protected and preserved.
The amount or direction provided by the inventor / the existence of working examples
The examples of the instant disclosure describe the preparation and assaying of anti-CD112R antibodies (Examples 1-8). The examples further describe pharmacodynamic evaluation of anti-CD112R antibodies, anti-TIGIT antibody, and combinations thereof on subcutaneous xenograft tumor models of human melanoma A375 mixed with PBMCs (Example 9, page 75). In the study, A375 and PBMC cells were inoculated subcutaneously on the right side of NCG mice. The day of the inoculation was day 0, and the mice were randomly divided into groups for drug administration at varying dosages. Results are reported in Table 14 on page 77. The example concludes that, at the end of the experiment (25 days after administration), the tested anti-CD112R antibody demonstrated significant tumor growth inhibition compared to the control and, in combination with JS006 (TIGIT antibody), showed a significant synergistic anti-tumor effect (page 77, lines 6-11).
While the examples demonstrate the use of an anti-CD112R antibody in combination with an anti-TIGIT antibody as a method of inhibiting tumor growth, the examples do not demonstrate cancer prevention using the claimed methods.
In particular, the disclosure does not demonstrate or identify a method that could be used to predictably determine that a subject would develop the claimed cancers in order to establish that the claimed method resulted in prevention of said cancers.
The state of the prior art / the level of predictability in the art
There are no art recognized methods that can be used to predictably determine that cancer onset was prevented using claimed method or to identify subjects who would predictably develop the claimed cancers in order to predictably identify that prevention was achieved using therapeutic approaches. Rather, the state of the art indicates that cancer development was not predictable.
Lewandowska, A.M., et al (2017) Environmental risk factors for cancer – review paper Ann. Agric. Environ. Med. 26(1); 1-7 teaches that the cancerous process is a result of disturbed cell function. This is due to the accumulation of many genetic and epigenetic changes within the cell, expressed in the accumulation of chromosomal or molecular aberrations, which leads to genetic instability. It is difficult to assess the validity of individual etiological factors, but it can be concluded that interaction of various risk factors has the largest contribution for the development of cancer. Environmental, exogenous and endogenous factors, as well as individual factors, including genetic predisposition, contribute to the development of cancer (page 1, right column, paragraph 1). Lewandowska discusses numerous factors that contribute to the development of cancer including physical factors such as exposure to electromagnetic fields, ionizing radiation, and ultraviolet radiation (pages 2-3); chemical factors including tobacco smoking, alcohol, and other chemicals (pages 3-4); and biological factors including diet, physical activity, mutagenic and carcinogenic compounds in food, nitrosoamines, and infections (pages 4-5). Lewandowska teaches that, additionally, some epidemiological research suggests that the influence of environmental factors will further affect the cell’s genetic material. This is connected with the spreading of carcinogens in various geographical zones. While some are well known and can be modified, there are certain factors that cannot be fully controlled, such as industrialization (page 6, left column, paragraph 2).
The teachings of Lewandowska demonstrate that, while it was known that cancer is caused by disturbed cell function, numerous factors had been identified that could lead to such disfunction and cell disfunction is likely caused by the interaction of various risk factors. Lewandowska also teaches factors such as genetic predisposition and environmental factors that can contribute to the formation of cancer but are beyond the control of an individual subject. These teachings demonstrate that there was no specific known cause of cancer and, therefore, suggest that there would be no method to predictably determine that cancer would have developed in order to establish that it was prevented.
Cuzick, J. (2017) Preventive therapy for cancer Lancet Oncol 18; e472- e482 teaches the use of therapeutic preventative measures in addition to weight control and physical activity, such as low-dose aspirin for adults without the risk of hypertension or gastrointestinal bleeding, universal HPV vaccination, and other therapies such as anti-oestrogen drugs for breast cancer prevention targeting high-risks groups to “maintain a favorable benefit-risk ratio” (abstract). While Cuzick is identifying therapeutic regimens to prevent cancer, Cuzick also teaches “the balance of risks and benefits is inherently more challenging for preventative than for therapeutic interventions. Only a small fraction of the apparently healthy people who receive a preventative treatment would ultimately develop the specific type of cancer being targeted. Moreover, the absence of the cancer is not quantifiable at an individual level, whereas all those treated will incur a risk of side-effects which are identifiable on an individual basis” (page e472, left column, paragraph 2).
Cuzick demonstrates that the prevention of cancer is not predictable and that numerous factors contribute to the development of cancer. Additionally, Cuzick teaches difficulties in preventing cancer with therapeutic methods and specifically states that the absence of cancer is not quantifiable on an individual level, a statement which demonstrates that the determination of whether or not cancer was prevented is unpredictable.
DeCensi, A., et al (2015) Barriers to preventative therapy for breast and other major cancers and strategies to improve uptake ecancer 9(595); 1-12 teaches that the global cancer burden continues to rise but the utilization of preventative therapy has been poor due to various barriers. DeCensi teaches barriers such as the lack of physician and patient awareness, fear of side effects, and licensing and indemnity issues. DeCensi provides a review discussing the barriers and proposes strategies to overcome them including improving awareness and countering prejudices by highlighting the important differences between preventative therapy and cancer treatment. DeCensi further teaches that future research to improve therapeutic cancer prevention needs to include improvements in the prediction of benefits and harms and improvements in safety profiles of existing agents by experimentation with dose (abstract). DeCensi teaches that for preventative therapy, we cannot identify individuals whose cancer was prevented or risk was substantially reduced because of the lack of measurable biomarkers of efficacy that currently exist for other diseases such as cardiovascular diseases, prevention of diabetes complications or osteoporotic bone fractures. Therefore, from that person’s point of view, they either took medication unnecessarily or, in the worst-case scenario, unnecessarily suffered the adverse effects of such therapy (page 2, paragraph 1).
The teachings of DeCensi demonstrate that, while preventative therapies could be beneficial if various barriers are overcome, there was no method known that could be used to identify individuals whose cancer was prevented because of the lack of measurable biomarkers.
The teachings of Lewandowska, Cuzick, and DeCensi demonstrate that there was no art recognized method of determining whether a subject would predictably develop cancer and, therefore, there is no predictable way to determine that cancer was prevented using the claimed method.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure
As discussed above, there is no disclosed or art recognized method through which an ordinarily skilled artisan would be able to determine that a mammal would have predictably developed cancer in order to apply the claimed treatment as a preventative measure. Furthermore, there is no known or disclosed method that could be used to establish that cancer was prevented as there is no predictable way to know that the subject being treated would have developed a cancer without the treatment. As such, in order to implement the invention as claimed, one of ordinary skill in the art would have to participate in undue experimentation to identify a method that could be used to establish that cancer was prevented, with the possibility that no such method could be found.
In view of the Wands factors discussed above, a person of ordinary skill in the art would have to engage in undue experimentation to practice the full scope of the claimed invention. As such, the instant claims were determined to not meet the scope of enablement requirement of 35 USC 112(a).
Written Description
Claims 1-12, 14-19, and 21 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.
Instant claim 1 is drawn to an anti-CD112R antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises HCDRs 1-3 and LCDRs 1-3 with the structures recited in the claim. The HCDRs 1-3 and LCDRs 1-3 recited in the claim allow for significant variance in the amino acid sequences. As such, the claim is drawn to a genus of antibodies or antigen binding fragments thereof comprising various CDRs all of which are claimed as performing the function of being an anti-CD112R antibody. Claim 16 and 18 both depend on claim 1 and further claim functions of the antibodies or antigen binding fragments thereof including their use in a method of preventing and/or treating cancer and a method for detecting the presence of CD112R in a sample.
Claim 2 is drawn to the anti-CD112R antibody or antigen binding fragment thereof and recites that the antibody or antigen binding fragment thereof comprises a heavy chain variable region or a light chain variable region with the recited sequences. Each of parts (I) – (XXI) include embodiments in which the heavy and light chain amino acid sequences have “at least 95%, 96%, 97%, 98%, or 99% sequence identity” to the recited amino acid sequences. As such, the claim is drawn to a genus of antibodies with the function of being an anti-CD112R antibody. Additionally, the claim recites “an” amino acid sequence as set forth in the recited sequences. In the broadest reasonable interpretation of the claim, “an” amino acid encompasses segments or portions of the recited sequences rather than the entire sequence further establishing the genus that is claimed.
Claim 3 is drawn to the antibody or antigen binding fragment thereof of claim 1 and recites heavy chain and light chain variable regions having “an” amino acid sequence set forth in the recited sequences. In the broadest reasonable interpretation of the claim, “an” amino acid encompasses segments or portions of the recited sequences rather than the entire sequence. As such, claim 3 remains drawn to a genus of antibodies or antigen binding fragments thereof, all of which are claimed to function as an anti-CD112R antibody or antigen binding fragment thereof.
Claim 19 is drawn to the antibody or antigen binding fragment thereof of claim 1 and recites HCDRs and LCDRs variable regions having “an” amino acid sequence set forth in the recited sequences. In the broadest reasonable interpretation of the claim, “an” amino acid encompasses segments or portions of the recited sequences rather than the entire sequence. As such, claim 19 remains drawn to a genus of antibodies or antigen binding fragments thereof, all of which are claimed to function as an anti-CD112R antibody or antigen binding fragment thereof.
Claim 21 is drawn to the antibody or antigen binding fragment thereof of claim 1 and recites heavy chain and light chain variable regions having “an” amino acid sequence as set forth in the recited sequences. In the broadest reasonable interpretation of the claim, “an” amino acid encompasses segments or portions of the recited sequences rather than the entire sequence. As such, claim 21 remains drawn to a genus of antibodies or antigen binding fragments thereof, all of which are claimed to function as an anti-CD112R antibody or antigen binding fragment thereof.
The instant claims are drawn to a genus of antibodies or antigen binding fragments thereof, all of which are claimed as at least functioning as an anti-CD112R antibody.
The instant disclosure, however, does not identify a representative number of species of the instantly claimed genus resulting in the claimed function, nor does the disclosure identify a structure-function correlation that could be used to predictably identify which CDR amino acid combinations of the instant claims could be used resulting in an antibody or antigen binding fragment thereof with the claimed functions. This is particularly the case in the absence of a full complement of 6 CDRs (three from the heavy chain variable region and three from the light chain variable region) with 100% sequence identity that is demonstrated as binding CD112R.
The examples of the instant disclosure detail the production and screening of anti-CD112R murine antibodies (Examples 1-4). The examples disclose 15 anti-CD112R murine antibodies, which were assayed and sequenced, the CDR and heavy and light chain variable regions of which are shown in Table 1. It is also noted that hybridoma cells 4E2 contained two heavy chains containing variable regions that are reported as 4E2-VH1 and 4E2-VH2, respectively (page 62, lines 11-14). Table 1 (pages 36-37) provide SEQ ID NOs for the CDRs and VH and VL of each of the antibodies and pages 38-44 provide the sequences. It is noted that it is not apparent from the specification whether 4E2-VH1 and 4E2-VH2 , when combined with 4E2-VL bind to CD112R, or if both heavy chains are required for binding.
The examples further detail the construction of chimeric antibodies in which the VH and VLs of the antibodies were combined, as shown in Table 2 on pages 45-46 (Example 5). The binding of these chimeric anti-CD112R antibodies to human CHO-CD112R expressing cells were tested and results are reported in table 6. Of these antibodies, chi- 61, 54, 55, 71, 62, 70, 69, 63, 47, 18, 36, 46, 53, 45, and 72 are shown to bind to CD112R expressing cells to some degree. Binding is reported as not detected for chi- 10 and 52.
The examples further detail the humanization of the antibody variable regions (page 68, Example 7). Humanization was performed based on the sequences of the obtained murine antibodies comprising steps of comparing the gene sequence of the murine antibody with that of the human embryonic antibody to find high homology; analyzing and inspecting HLA-DR affinity; selecting a human embryonic framework sequence with low affinity; and analyzing the framework amino acid sequences in the variable regions and their periphery by using computer simulation and molecular docking. Key amino acid individuals that may interact with human CD112R and maintain spatial framework were analyzed by calculating various forces and grafted to the selected human embryonic gene framework. The numbers and amino acid sequences of the humanized antibodies are shown in detail in Table 3. It is noted that, described, the humanization is in the framework regions that do not interact with CD112R binding, indicating that the humanized antibodies maintain the murine antibody CDRs.
The 15 anti-CD112R antibodies obtained from isolation and screening, as well as the chimeric combinations that are demonstrated as binding to CD112R in the disclosure, with a full complement of 6 CDRs (3 from the light and 3 from the heavy chain variable regions) with 100% identity, represent the antibodies that applicant was in possession of at the time of the instant filing date of the claimed invention. It is noted that not all of these antibodies are species of the instantly claimed invention which limit the CDRs of the antibodies claimed as recited in claim 1.
These species are not representative of the full scope of the instantly claimed genus in which the CDRs comprise various combinations of amino acid sequences. The disclosure also does not provide a sufficient structure function correlation that would allow for the predictable identification of which amino acid sequences in the CDRs could be used while maintaining CD112R binding.
The disclosure does discuss conservative and non-conservative substitutions that do not significantly alter bioactivity, referred to as “conservative variants” or function-conservative variants” of the antibody (page 20). With regard to the instantly claimed variable amino acids, the instant disclosure discusses that substitutions N, T, S, etc. are all polar and uncharged aliphatic amino acids; S, R, N, D, etc., are polar aliphatic amino acids; D, G, V, I, etc., are all aliphatic amino acids; L, P, etc., are all non-polar amino acids; Y, F, etc., are all aromatic amino acids; Y, S, etc., are all polar and uncharged amino acids; N, Q, H, etc., are all polar amino acids; H, R, etc., are all polar charged amino acids. Thus, these amino acids can be substituted with each other, and the obtained CDRs retain the binding activity described herein when used to construct an anti-CD112R antibody.
The disclosure, however, does not demonstrate the full scope of these substitutions nor does the disclosure demonstrate that these amino acid substitutions in the CDRs would retain the binding activity to CD112R as suggested. Rather, the prior art suggest that, even conservative amino acid substitutions are not predictable, as discussed in detail below.
The prior art also does not provide a representative number of species of the claimed genus binding to CD112R, nor does the prior art provide a structure function relationship that could be used to predictably identify which combinations of CDRs, with what amino acid sequences, would retain this binding. Rather, the art suggests that antibody structure-function is not predictable.
For instance, Chiu, M.L., et al (2019) Antibody structure and function: The basis for engineering therapeutics Antibodies 8(55); 1-80 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. Chiu teaches that 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). These teachings of Chiu demonstrate that the interaction between the heavy and light chain variable domains effect the conformation of the binding region of the antibody and therefore the antibody’s ability to bind to its target. Furthermore, 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. Based on these teachings, an ordinarily skilled artisan would not have been able to predictably identify which species of the instantly claimed genus would be capable of performing the claimed function. This is particularly the case in the absence of a full complement of heavy and light chain CDRs.
Rabia, L., et al (2018) Understanding and overcoming trade-offs between antibody affinity, specificity, stability, and solubility Biochem Eng. J. 15(137); 365-374 discusses challenges faced during antibody optimization. Rabia discusses the challenges with optimizing antibody properties and states 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).
Based on the teachings of Rabia, introducing mutations in the antibody structure, particularly in the CDR regions, is not a predictable task and requires experimentation following mutation to ensure that the binding affinity is maintained and a specific, stable antibody is created. Rabia further spoke to the use of libraries and computational methods for predicting and co-optimizing antibody properties and teaches that these methods are not robust enough yet to yield predictable results. These teachings demonstrate that a modification to even one amino acid of an antibody, particularly in the CDRs, would likely result in an antibody that is not suitable for binding as recited in the instant claims.
Rojas, G. (2022) Understanding and Modulating Antibody Fine Specificity: Lessons from Combinatorial Biology Antibodies 11(48); 1-22, which was published approximately a year after the effective filing date of the claimed invention, demonstrates that antibody structure and function were still not predictable. For instance, Rojas teaches that epitope mapping results using mutagenesis scanning challenge our notions of conservative and nonconservative amino acid replacements. Several measures have been proposed to evaluate the difference between amino acids, based on physico-chemical distance between them, mutational distance, or evolutionary exchangeability. Tolerability profile to mutations within functional epitopes does not adjust strictly to any of these rules. The critical attributes of each amino acid that should be kept to maintain recognition depend on the particular antibody. For instance, sometimes only tyrosine and phenylalanine residues can be exchanged without effecting antigenicity, pointing to the relevance of their almost-identical aromatic rings, whereas in other epitopes, tyrosine and histidine are exchangeable, reflecting that two different rings can fulfill a similar functional role (page 11, paragraph 1). Teachings which demonstrate that even years after the effective filing date of the claimed invention even modifications using conservative substitution were not predictable.
It is not evident from the disclosure, or the prior art, that applicant was in possession of a representative number of species supporting the entire genus of antibodies that are encompassed by the instant the claims. Additionally, there is no disclosed or art recognized structure-function relationship between antibody structure and functionality which would allow for the predictable substitution of amino acids in the claimed sequences while maintaining binding function. Therefore, the instant claims were found to not meet the written description requirement.
It is noted that there is support for variation in the heavy and light chain variable regions of the antibody if the full complement of 6 CDRs were limited to 100% identity.
Claim 4 is 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.
Instant claim 4 is drawn to the antibody or antigen-binding fragment thereof of claim 1, and encompasses an embodiment in which the antibody or antigen-binding fragment thereof is a fully human antibody. Fully human antibodies, however, are not described in the specification in such a way as to reasonably convey to one of ordinary skill in the art that applicant was in possession of the claimed fully human antibodies at the time of the effective filing date of the claimed invention.
The instant disclosure defines fully human antibody as referring to an antibody that comprises only human immunoglobulin sequences (page 21, lines 30-31).
The antibodies of the instant invention, from which the HCDRs and LCDRs of claim 1 were derived, however, do not appear to be produced using methods that would result in fully human antibodies. The examples of the instant specification detail the production of the antibodies. Example 2 explains that BALB/c mice were immunized with a hCD112R-Fc using a prime boost immunization method. Mouse hybridoma cells were then screened and anti-CD112R murine antibodies were assayed (Example 3). From these, 8 candidate monoclonal antibodies were identified. The antibodies were sequenced and the CDRs and heavy and light chain variable regions are shown in Table 1 (page 62, lines 11-14). Based on the disclosure, and the methods used to isolate the antibodies of the instant disclosure, the antibodies are murine, or mouse derived. As such, it is not evident that the HCDRs and LCDRs of claim 1 are human CDRs or that the CDRs could be used to form a fully human antibody or antigen binding fragment thereof that comprises only human immunoglobulin sequences. It is not evident from the disclosure that applicant was in possession of even a single species of fully human antibody. Furthermore, the disclosure does not describe a method that could be used to produce functioning, fully human antibodies from murine CDRs.
The definition of “fully human antibody” used by applicant is in agreement with the common definition of the art, which also demonstrates that, in order to be a fully human antibody, the sequence must be fully human with no murine sequences. For instance, Harding, F.A., et al (2010) The immunogenicity of humanized and fully human antibodies mAbs 2(3); 256-265 teaches that fully human sequence derived antibodies have no murine sequence, and are largely produced via two sources: phage display technology and transgenic mice. Recently, fully human sequence antibodies isolated from mice carrying genetic modifications such that the murine immunoglobulin genes were disabled and replaced with functional human immunoglobulin loci have been approved for therapeutic use (page 258, right column, paragraph 2). While Harding does disclose methods by which fully human antibodies can be produced by mice, specifically transgenic mice with genetic modifications, it is not evident from the instant disclosure that such mice were used.
Overall, the antibodies of the instant disclosure, and therefore the CDRs of instant claim 1, were derived from murine antibodies. The instant disclosure does not appear to provide even a single species of the claimed fully human antibodies nor does the prior art. The disclosure and prior art also do not provide a method through which murine CDRs could be used to form fully human antibodies comprising no murine sequences. As such, one of ordinary skill in the art would not reasonably recognize that applicant was in possession of the full scope of the claims at the time of the effective filing date and; therefore, the embodiment of claim 4 in which the antibody is a fully human antibody does not meet the written description requirement of 35 USC 112(a).
Claim 6 is 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.
Claim 6 is drawn to an isolated anti-CD112R antibody or antigen binding fragment thereof having at least of the two recited properties which include binding to an epitope of human CD112 which is identical to, or completely or partially overlaps with an epitope to which the antibody or antigen binding fragment of claim 1 binds; or competing for binding to an epitope of human CD112R protein with the antibody or antigen binding fragment thereof of claim 1.
The instant claim recites functional limitations and claim a genus of antibodies by what they do (function), rather than by what they are (structure).
MPEP 2173.05(g) teaches that “Unlimited functional claim limitations that extend to all means or methods of resolving a problem may not be adequately supported by the written description or may not be commensurate in scope with the enabling disclosure, both of which are required by 35 U.S.C. 112(a) and pre-AIA 35 U.S.C. 112, first paragraph. In re Hyatt, 708 F.2d 712, 714, 218 USPQ 195, 197 (Fed. Cir. 1983); Ariad, 598 F.3d at 1340, 94 USPQ2d at 1167. For instance, a single means claim covering every conceivable means for achieving the stated result was held to be invalid under 35 U.S.C. 112, first paragraph because the court recognized that the specification, which disclosed only those means known to the inventor, was not commensurate in scope with the claim. Hyatt, 708 F.2d at 714-715, 218 USPQ at 197.”
In this case, the antibodies claimed are based on the epitope to which they bind and competitive binding, not the structure of the antibodies that would result in the claimed functions.
The instant disclosure does not provide a sufficient number of species of the claimed genus nor does it adequately describe the structure required to achieve the claimed function in such a way as to demonstrate to an ordinarily skilled artisan that applicant was in possession of the genus as claimed at the time of filing.
The disclosure defines “epitope” as referring to a protein determinant capable of specific binding to an antibody. Epitopes are usually composed of a variety of chemically active surface molecules, such as amino acids or sugar side chains and usually have specific three dimensional structural characteristics as well as specific charge characteristics (page 22, lines 13-18). As discussed above, the disclosure details the production and screening of 15 anti-CD112R antibodies, as well as chimeric antibodies and humanized antibodies derived therefrom. The examples do not provide epitope binding data for these antibodies nor does the disclosure identify a single species of antibody that binds to an epitope of human CD112R that is identical to, or completely or partially overlapping with the antibodies of the instant claims. The disclosure also does not identify a structure-function relationship that could be used to identify which antibodies, having what structure, would bind to the same or overlapping epitopes as those claimed.
Similarly, the examples of the disclosure do not demonstrate or disclose a single species of antibody that competes for binding to an epitope of human CD112R with the claimed antibody. The disclosure also does not provide a structure-function correlation that could be used to identify which antibodies, having what structure, would compete for epitope binding with the claimed antibodies.
The prior art also does not provide a representative number of species of antibodies having the claimed function nor does the prior art provide a structure-function correlation that could be used to identify such antibodies. Rather, the teaching of the prior art demonstrate that epitope binding and competitive binding was, and is, not predictable.
For instance, Hummer, A.M., et al (2022) Advances in computational structure-based antibody design Current Opinion in Structural Biology 74(102379); 1-7 teaches that traditional methods for antibody development, such as deriving antibodies from hybridomas of inoculated animals or from library assembly followed by display techniques are not only costly and time consuming but also are not necessarily able to produce antibodies that bind to the desired site (epitope) on an antigen. Hummer teaches that computational antibody design methods offer a way to overcome these limitations, but are held back by the lack of accurate antibody and antigen structures (page 1, right column, paragraph 2). Hummer provides a review on how advances in protein structure prediction and other areas are bringing us closer to being able to entirely computationally designed antibodies that bind strongly to a defined epitope (page 1, right column, paragraph 3), demonstrating that in 2022 predictable structure function relationships were still not known. Hummer acknowledges this in their discussion of future directions stating that “Several challenges still remain for true computational structure-based antibody design. While there has been great progress in protein structure prediction, current methods are not yet able to accurately predict the position of the side chain atoms or structural changes on binding. For antibodies, accurately modeling the CDR-H3 loop remains a major obstacle. Additionally, improvements in paratope and epitope prediction, both in terms of accuracy and specificity (predicting the types of binding interactions for residues), will be needed to help improve docking for high-throughput virtual screening.” (page 4, right column, paragraph 3).
Overall, Hummer teaches the difficulties in predicting the relationship between antibody structure and the epitopes to which they bind demonstrating a lack of predictability in the field between antibody structure and function.
Chan, B.M., et al (2018) Flow cytometry-based epitope binning using competitive binding profiles for the characterization of monoclonal antibodies against cellular and soluble protein targets SLAS Discovery 23(7); 613-623 teaches that a successful therapeutic antibody drug discovery process requires rigorous molecule selection to ensure that a molecule can be manufactured and is also maximally efficacious in the clinic. The selection process typically includes screens to characterize binding properties, including affinity and selectivity, and whenever possible, a screen to assess activity. In addition, epitope information can often complement or even drive the selection strategy. The epitope is characteristic of an antibody’s functional capacity and is an innate property that cannot be engineered, unlike its affinity (page 613, left column, paragraph 1). Chan further teaches that traditional methods of epitope binning include enzyme linked immunosorbent assay (ELISA) (page 614, left column, paragraph 3) and teaches methods of epitope binning that generate competitive binding profiles for antibody panels against reference antibodies through flow cytometry platforms (page 614, left column, paragraph 5). Chan teaches that epitope binning techniques and platforms are continuously evolving and that they can range from epitope mapping of an antibody’s binding site to its antigen at high resolution, to simple ELISA-based competition assays (page 622, left column, paragraph 2).
The teachings of Chan demonstrate that competitive binding is used as a means of comparing binding epitopes and that such a property could not be engineered.
Overall, it is not evident by the disclosure, or the prior art, that applicant was in possession of a representative number of species of antibodies which bind to the same or overlapping epitopes as, or compete for binding with, the antibodies of the instant claims. Furthermore, as discussed above, there is no disclosed or art recognized correlation between structure and function which would allow for the predictable generation or identification of antibodies that bind to the same or overlapping epitopes or compete for binding with the claimed antibodies. Therefore, the instant claims were found not to meet the written description requirement of 35 USC 112(a).
Allowable Subject Matter
Claim 20 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following is a statement of reasons for the indication of allowable subject matter: The instant claim is drawn to the antibody or antigen binding fragment of claim 1 and further limits the heavy and light chain variable regions to comprising the recited HCDR and LCDR combinations. In searches of the prior art, no CDR combinations matching those of the instant claim were found. The following is considered to be the closest prior art:
WO 2013/190555 A1 (Cojocaru, G.S., et al) 27 Dec 2013
WO’555 teaches antibodies and antigen binding fragments specific for LSR molecules, which are suitable for immunotherapy and treatment of specific cancers (abstract).
WO’555 teaches an antibody, 8C8, having a heavy chain variable region SEQ ID NO: 218 (pages 160-161). WO’555 has the following alignment with instant SEQ ID NOs: 67-69, respectively.
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As shown, WO’555 SEQ ID NO: 218 comprises significant misalignment within the instantly claimed CDRs. Additionally, the antibody disclosed by WO’555 binds to lipolysis stimulated lipoprotein receptor (LSR), not CD112R as claimed.
In prior art searches of the instantly claimed CDR combinations, no matching structures were identified. Based on the nature of antibody functionality and the sensitivity of antibody affinity to variations in the amino acid sequences, particularly in the CDRs, it would not have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the teachings of WO’555 to arrive at the antibody structures claimed without undergoing a significant amount of trial and error experimentation. Therefore, the instantly claimed CDR combinations were found to be novel and non-obvious.
Conclusion
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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693
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