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 05/06/2023, is a continuation of PCT/CN2021/134134, filed 11/29/2021, which is a continuation in part of PCT/CN2020/132111, filed 11/27/2020.
Status of Claims/Application
Claims 1-15 are currently pending and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 05/01/2025 is in compliance with the provisions of 37 CFR 1.97, except where noted below. Accordingly, the information disclosure statement has been considered by the examiner.
A copy of NPL reference number 4, Zhao et al., was not identified in the file wrapper in accordance with 37 CFR 1.97. The reference has been lined through on the IDS and has not been considered.
Nucleotide and/or Amino Acid Sequence Disclosures
In the specification, [0002], the ASCII size is provided in KB rather than in the required bytes. See 1.a.iii and 1.b.iii below.
In the specification “G4S” is recited in the following locations without an appropriate SEQ ID NO: [0026], line 3; and Table 2, description column, all rows.
Claim 5 recites “G4S”, representing the sequence GGGGS, without an appropriate SEQ ID NO.
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.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 11 is rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. The claim(s) does/do not fall within at least one of the four categories of patent eligible subject matter because the claim is a “use” claim. MPEP 2173.05 (q) states “’Use’ claims that do not purport to claim a process, machine, manufacture, or composition of matter fail to comply with 35 U.S.C. 101.”
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 10-11 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 10 recites “the two or more single domain anti-LAG3 antibodies”. There is insufficient antecedent basis for this limitation in the claim. The claim depends on claim 9 which recites one or more single domain anti-LAG3 antibodies and does not specifically recite two or more single domain anti-LAG3 antibodies that could be being referenced.
Claim 11 recites use of the single domain antibody of claim 1 in manufacturing a medicament for the treating or preventing the claimed cancer types in a subject. The claim attempts to claim a process without setting forth any steps involved in the process rendering the claim indefinite. See MPEP 2173.05(q).
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 3 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 3 depends on claim 2 and recites the limitation that one or more DG of one or more CDRs are mutated to DA and/or EG, and/or one or more NG of one or more CDRs are mutated to NA and/or QG. As such, claim 3 encompasses embodiments in which the CDRs recited in claim 2 are modified. As claim 2 requires CDRs with 100% identity, claim 3 is broader than claim 2 and fails to 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) – Scope of Enablement
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 11-15 are 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 the recited cancers, does not reasonably provide enablement for preventing the recited cancers. 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 11 encompasses the use of the single domain anti-LAG3 antibody of claim 1 in manufacturing a medication for preventing the cancers recited in the claim.
Claims 12-14 encompass a method of preventing one or more conditions of a subject comprising administering a therapeutically effective amount of one or more single domain anti-LAG3 antibodies, wherein the one or more conditions are selected from the recited cancers.
Claim 15 encompasses a method of preventing one or more of the recited cancers in a subject comprising administering a therapeutically effective amount of a pharmaceutical composition comprising single domain anti-LAG3 antibodies.
The breadth of the claims
The claims are broad in that they encompass the 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, preventing the recited cancers indicates that that the onset of the cancer 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 disclose the generation and optimization of anti-LAG3 single domain antibodies (Examples 1-6 and 8-9). The examples further demonstrate the effects of single domain antibodies on Jurkat T cells overexpressing human LAG3 and Raji B cells (Example 7) and on hLAG3-His protein (Example 10).
The examples do not demonstrate prevention of the cancers recited in the instant claims. The disclosure also does not identify, or demonstrate through working examples, a method that can be used by one of ordinary skill in the art to predictably determine that a subject would develop one of the claimed cancers in order to establish that cancer was prevented using the claimed method.
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 patients who would predictably develop cancer in order to 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 patient 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 subject would have predictably developed one of the claimed cancers 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).
Claim Rejections - 35 USC § 112(a) – Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-15 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.
Claim 1 is drawn to a single domain anti-LAG3 antibody that specifically binds LAG3 and encompasses sequences comprising “an” amino acid sequence selected from the group of SEQ ID NOs: 1-19, 80-86, and 89-97, or an amino acid sequence that is “at least 85%, at least 90%, at least 95%, at least 98%, or at least 90% identical” to “a” sequence selected from the group of SEQ ID NOs: 1-19, 80-86, and 89-97. Claims 11-15 further claim the use of the antibodies in methods of treating or preventing cancer. In the broadest reasonable interpretation of “an” amino acid sequence and “a” amino acid sequence, the claim encompasses amino acid sequences that comprise as little as two amino acids from within the recited sequences. Additionally, based on the claimed identity percentages, claim 1 encompasses a genus of single domain anti-LAG3 antibodies with modifications to the recited sequences, all of which are claimed to function in specifically binding to human LAG3 and being capable of treating or preventing cancer.
Claim 2 is drawn to a single domain anti-LAG3 antibody that specifically binds human LAG3, wherein the antibody comprises a CDR1 selected from the recited sequences, a CDR2 selected from the recited sequences “and/or” a CDR3 selected from the recited sequences. The claim encompasses a genus of anti-LAG3 antibodies, limited by as little as a single CDR, as well as anti-LAG3 antibodies with varying combinations of CDRs, all of which are claimed as having the function of specifically binding to human LAG-3.
Claim 3, which depends on claim 2, recites CDR sequences for the anti-LAG3 antibodies but allows for the combination of various CDRs 1-3. The claim also uses the conjunction “and/or” indicating that the anti-LAG3 antibody is only required to include one of the recited CDRs. Claim 3 further recites that one or more DG of one or more CDRs is mutated to DA and/or EG, and or one or more NG of one or more CDRs are mutated to NA and/or DG. Claim 3 encompasses a genus of antibodies, limited by as little as a single CDR which can also have modifications as claimed, all of which are claimed as performing the function of specifically binding to human LAG3.
Claim 8 is drawn to a single domain antibody fusion comprising the amino acid sequence selected from the group consisting of SEQ ID NOs: 58-76, or an amino acid sequence that is “at least 85%, at least 90%, at least 95%, at least 98%, or at least 90% identical” to “a” sequence selected from the group of SEQ ID NOs: 58-76. In the broadest reasonable interpretation of “a” amino acid sequence, the claim encompasses amino acid sequences that comprise as little as two amino acids from within the recited sequences. Based on the use of “a” sequence and the claimed identity percentages, claim 8 encompasses a genus of single domain antibody fusions all of which are claimed as functioning as an antibody fusion which indicates that the claimed fusion must bind to something.
The instant claims are drawn to a genus of anti-LAG3 antibodies and fusion antibodies all of which are claimed as having the recited functions as discussed in detail above. The instant disclosure, however, does not demonstrate a representative number of species of the claimed genus performing the claimed functions. The disclosure also does not provide a structure-function correlation that could be used to predictably identify which species of the claimed genus would be capable of performing the claimed function, particularly in the absence of a full complement of CDRs (three for single domain antibodies), which are the art recognized binding sites of antibodies.
The examples disclose the generation and optimization of anti-LAG3 single domain antibodies (Examples 1-6 and 8-9). The examples further demonstrate the effects of single domain antibodies on Jurkat T cells overexpressing human LAG3 and Raji B cells (Example 7) and on hLAG3-His protein (Example 10). The specification provides sequences of single domain antibodies, and their 3 CDRs, in Table 1 (pages 6-9), Table 13 (pages 29-32), and Table 19 (pages 38-40) as well as sdAb fusion sequences in Table 2 (pages 9-13).
These single domain antibodies and fusion sequences, with the full complement of 3 CDRs with 100% identity in the CDRs, represents the single domain antibodies and fusions thereof that applicant was in possession of at the time of the effective filing date.
The prior art also does not provide a representative number of species of the claimed genus nor does the prior art provide a structure function correlation that can be used to predictably identify which species of the claimed genus would perform the functions claimed. Rather, the state of the art suggests that antibody structure-function is not predictable, particularly in the absence of a full complement of CDRs.
Bathula, N.V., et al (2021) Nanobodies: The future of antibody-based immune therapeutics Cancer biotherapy and radiopharmaceuticals 36; 109-122 teaches that crystallography studies revealed many dynamic features of VHH domain antibodies, such as it is composed of four framework regions (FR) with nine β-sheets separated by loops, which include three hypervariable regions, or CDRs (page 110, right column). The CDR1, located towards the N-terminal region, has high variability, but nonetheless contributes to the binding strength of the domain in collaboration with CDR2, particularly by formation of an interloop disulfide bond with CDR3. The CDR3 is mainly engaged in antigen recognition and is longer than in the conventional VH domain. The longer CD3 gives increased flexibility for antigen binding and specificity variations. Furthermore, in many nanobodies, CDR3 domains have protruding ends, which improves their ability to reach and interact with the epitopes located in protein crevices and enzyme-active domains. All of these properties contribute to the convex surface of VHH, which supplements its ability to interact with the antigen cavities (page 111, left column, paragraph 3).
Hoey, R.J., et al (2019) Structure and development of single domain antibodies as modules for therapeutics and diagnostics Experimental biology and medicine 244; 1568-1576 teaches that VHH domains typically rely heavily on CDR3 for interactions with antigens. Notably, an elongated CDR3 loop provides VHH significant versatility in its ability to interact with target molecules. Unlike conventional antibodies, VHH domains have been observed to interact with antigens in protruding/extended conformations, which allow the antibody to bind protein clefts/pockets, including enzyme active sites. In addition, the CDR3 loop can produce a structurally flat paratope using CDR1/3, CDR1/2/3, and CDR2/3/FW, with some possessing more convex or concave paratopes (paragraph bridging columns, page 1569).
The teachings of Bathula and Hoey demonstrate that antigen binding specificity and strength of single domain antibodies depends on the full complement 3 CDRs all of which, together, form the paratope of the binding domain.
Rojas, G. (2022) Understanding and Modulating Antibody Fine Specificity: Lessons from Combinatorial Biology Antibodies 11(48); 1-22, which was published approximately two years after the effective filing date of the claimed invention, demonstrates that antibody structure and function were still not predictable years after the effective filing date. 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, modifications, even those using conservative substitutions, 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 single domain anti-LAG3 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 modification of the claimed sequences while maintaining LAG3 binding function. Therefore, the instant claims are found to not meet the written description requirement.
It is noted that there would be support for variation in the framework regions if the full complement of 3 CDRs were limited to 100% identity.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-2, and 9 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US 2023/0340157 A1 (Liang, Y.) 26 OCT 2023, priority to 28 SEPT 2020.
US’157 teaches variable heavy (VHH) domain antibodies having an antigen binding specificity for human LAG3, wherein the VHH domains have the amino acid sequences of SEQ ID NOs: 84-85 (page 24, [0291]; claim 1). US’157 SEQ ID NOs: 84-85 are species of the instantly claimed single domain antibodies as follows:
US’157, SEQ ID NO: 84 has 88.3% identity with instant SEQ ID NO: 9 as shown in the ABSS alignment below. The sequence also comprises a sequence matching instantly claimed SEQ ID NO: 21 (underlined in the alignment):
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US’157, SEQ ID NO: 84 also has 88.9% identity with instant SEQ ID NO: 10 as shown in the ABSS alignment below. The sequence also comprises a sequence matching instantly claimed SEQ ID NOs: 21 and 33 (underlined in the alignment):
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621
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US’157, SEQ ID NO: 84 also has 88.9% identity with instant SEQ ID NO: 14 as shown in the ABSS alignment below. The sequence also comprises a sequence matching instantly claimed SEQ ID NOs: 21 and 33 (underlined in the alignment):
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321
618
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US’157, SEQ ID NO: 84 also has 87.0% identity with instant SEQ ID NO: 15 as shown in the ABSS alignment below:
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320
623
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US’157, SEQ ID NO: 85 has 94.6% identity with instant SEQ ID NO: 9 as shown in the ABSS alignment below. The sequence also comprises a sequence matching instantly claimed SEQ ID NO: 21 (underlined in the alignment):
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321
623
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US’157, SEQ ID NO: 85 also has 91.6% identity with instant SEQ ID NO: 10 as shown in the ABSS alignment below. The sequence also comprises a sequence matching instantly claimed SEQ ID NO: 21 (underlined in the alignment):
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314
619
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US’157, SEQ ID NO: 85 also has 91.6% identity with instant SEQ ID NO: 14 as shown in the ABSS alignment below. The sequence also comprises a sequence matching instantly claimed SEQ ID NO: 21 (underlined in the alignment):
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US’157, SEQ ID NO: 85 also has 89.7% identity with instant SEQ ID NO: 15 as shown in the ABSS alignment below:
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315
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US’157 further teaches pharmaceutical compositions comprising a therapeutically effective amount of the antibodies (page 10, [0118]).
Thus, US’157 anticipates the instant claims.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2, 4-6, 9, and 11-15 are rejected under 35 U.S.C. 103 as being unpatentable over US 2023/0340157 A1 (Liang, Y.) 26 OCT 2023, priority to 28 SEPT 2020.
The teachings of US’157 are as discussed in detail above.
US’157, however, does not exemplify a fusion comprising two or more single domain anti-LAG3 antibodies as recited in claims 4-6 or a method of treating the claimed cancers comprising administering the anti-LAG3 antibodies. The use of the anti-LAG3 VHH in a fusion protein or in methods of treating the claimed cancers, however, would have been obvious in view of the teachings of US’157 as a whole.
For instance, US’157 further teaches that the pharmaceutical compositions can contain one or more active agents and may further contain solvents, buffers diluents, carriers, and other excipients (page 10, [0119]). US’157 further teaches methods of treating cancer comprising administering the pharmaceutical composition to a patient in need thereof page 14, [0154]-[0155]). US’157 teaches that the cancer that can be treated includes lymphomas, non-small cell lung cancer, gastric cancer, hepatocellular cancer, bladder cancer, squamous neck cancer, and melanoma (page 14, [0156]).
US’157 further teaches multivalent single chain antibodies incorporating two or more monospecific heavy chain only antibodies (HCAb), wherein the two or more HCAb variable domains have specificity for different epitopes of the same antigen. That is, they are multivalent, but multi-specific with respect to epitope (page 2, [0037]-[0038]). US’157 further teaches some embodiments comprising two (or more) VHH domains with specificity for the same antigen joined in a single amino acid chain (page 1, [0005]). US’157 further teaches linkers for fusing the single chain antibodies including (G4S)n (page 25, Table 15, L4). US’157 further teaches that the VHH or bivalent domains are fused to one or more constant domains from a conventional antibody, for example, the Fc region of a human IgG antibody (page 1, [0004]).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify US’157 to include the VHH of SEQ ID NOs: 84 and 85 to be in a fusion protein for inclusion in a pharmaceutical composition or for administration to a subject for the treatment of cancer based on the teachings of US’157 as a whole. It would have been obvious to include the sequences in a fusion protein and an ordinarily skilled artisan would have had a reasonable expectation of success because US’157 teaches that the VHH antibodies disclosed can be used in fusion proteins and used in methods of treating cancer.
Conclusion
No claims are allowed.
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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693