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 .
Applicant's preliminary amendment, dated April 18, 2024, has been received. By way of this submission, Applicant has amended claims 2-7 and 9-12, and introduced new claims 13-20.
Claims 1-20 are pending in the application and under examination before the Office.
Priority
The certified copy of the foreign priority document submitted in the application on April 8, 2024 is in Chinese. As such, Applicant cannot rely upon the certified copy of the foreign priority application to overcome rejections because a translation of said application has not been made of record in accordance with 37 CFR 1.55. When an English language translation of a non-English language foreign application is required, the translation must be that of the certified copy (of the foreign application as filed) submitted together with a statement that the translation of the certified copy is accurate. See MPEP 215 and 216.
Therefore, for the purposes of the prior art, the effective filing date is March 21, 2022, the filing date of the United States application.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-2, 7-11 and 13 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.
"[T]he purpose of the written description requirement is to 'ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor's contribution to the field of art as described in the patent specification.'" Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Regents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). The recitation of a functional property alone, which must be shared by the members of the genus, is merely descriptive of what the members of the genus must be capable of doing, not of the substance and structure of the members. The Federal Circuit has cautioned that, for claims reciting a genus of antibodies with particular functional properties (e.g., high affinity, neutralization activity, competing with a reference antibody for binding), "[c]laiming antibodies with specific properties, e.g., an antibody that binds to human TNF-α with A2 specificity, can result in a claim that does not meet written description even if the human TNF-α protein is disclosed because antibodies with those properties have not been adequately described." Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875, 1877-78 (Fed. Cir. 2011).
"[A] sufficient description of a genus ... requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can 'visualize or recognize' the members of the genus." Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). A "representative number of species" means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) ("The '128 and '485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the genus."). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number" of species.
The "structural features common to the members of the genus" needed for one of skill in the art to 'visualize or recognize' the members of the genus takes into account the state of the art at the time of the invention. For antibodies, the Federal Circuit has found that possession of a mouse antibody heavy and light chain variable regions provides a structural "stepping stone" to the corresponding chimeric antibody, but not to human antibodies. Centocor, 97 USPQ2d at 1875 ("[T]he application only provides amino acid sequence information (a molecular description of the antibody) for a single mouse variable region, i.e., the variable region that the mouse A2 antibody and the chimeric antibody have in common. However, the mouse variable region sequence does not serve as a stepping stone to identifying a human variable region within the scope of the claims."). A chimeric antibody shares the full heavy and light chain variable regions with the corresponding mouse antibody; that is, the structure shared between a mouse and chimeric antibody would generally be expected to conserve the antigen binding activity.
Lastly, even if a selection procedure is disclosed that was, at the time of the invention, sufficient to enable the skilled artisan to identify antibodies with the recited functional properties, the written description provision of 35 U.S.C § 112 is severable from its enablement provision. Ariad, 94 USPQ2d at 1167; Centocor at 1876 ("The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.")
In Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc. v. Eli Lily & Co., 94 USPQ2d 1161 (Fed Cir. 2010), it is noted that to show invention, a patentee must convey in its disclosure that is "had possession of the claimed subject matter as of the filing date. Demonstrating possession "requires a precise definition" of the invention. To provide this precise definition" for a claim to a genus, a patentee must disclose "a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus" (see Amgen at page 1358).
Also, it is not enough for the specification to show how to make and use the invention, i.e., to enable it (see Amgen at page 1361).
An adequate written description must contain enough information about the actual makeup of the claimed products – "a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials", which may be present in "functional terminology when the art has established a correlation between structure and function" (Amgen page 1361).
On 22 February 2018, the USPTO provided a Memorandum clarifying the Written Description Guidelines for claims drawn to antibodies, which can be found at www.uspto.gov/sltes/default/files/docurrienfcs/amgenJ22feb2018.pdf. That Memorandum indicates that, in compliance with recent legal decisions, the disclosure of a fully characterized antigen no longer is sufficient written description of an antibody to that antigen.
In the instant case, the specification discloses a bispecific antibody that binds to CD47 and CLDN18.2 with its first and second antigen binding portions, respectively. However, the claims only recite structure for the CD47-binding portion of the bispecific antibody. The present claims attempt to claim every anti-CLDN18.2 antigen-binding domain, wherein the instant specification does not describe representative examples to support the full scope of the claims because the instant specification discloses only one exemplary antigen-binding domain. The instant disclosure, including the claims fail to disclose a representative number of species falling with the scope of the genus or structure common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus of the claimed anti-CLDN18.2 antigen-binding domain.
A "representative number of species" means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014).
Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. The "structural features common to the members of the genus" needed for one of skill in the art to 'visualize or recognize' the members of the genus takes into account the state of the art at the time of the invention. For example, the Federal Circuit has found that possession of a mouse antibody heavy and light chain variable regions provides a structural "stepping stone" to the corresponding chimeric antibody, but not to human antibodies. Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875 (Fed. Cir. 2011).
Here, the claims are directed to a genus of antigen-binding immunoglobulin molecules are defined by their desired binding to an antigen and function of such binding.
It is well-known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope. For example, Lloyd teaches that over hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (Protein Eng Des Sel. 2009 Mar;22(3):159-68; see page 159, right column, first paragraph: "Selection of such libraries to a given antigen can give rise to several hundreds to thousands of different antibodies.") The high degree of polymorphism in antibody generation evidences a lack of structure-function correlation for antibodies.
Given the well-known high level of polymorphism of immunoglobulins / antibodies, the skilled artisan would not have been in possession of the vast repertoire of antibodies encompassed by the claimed invention; one of skill in the art would conclude that applicant was not in possession of the structural attributes of a representative number of species possessed by the members of the genera of antibody that binds CLDN18.2 broadly encompassed by the claimed invention. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genera.
Applicant is invited to incorporate the subject matter of claim 3 into claim 1 in order to address this issue.
Claim 12 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Claim 12 is drawn to a method of treating cancer, comprising administering a bispecific antibody capable of binding CD47 and CLDN18.2. This term is constructed to mean treatment of any and every possible cancer, including blood cancer and metastatic cancer (see pages 21-22 of the instant specification). However, the instant specification as filed, does not provide sufficient enabling description for treating every possible cancer as encompassed by the claim because there does not appear to be sufficient in vitro or in vivo evidence to support administering a bispecific antibody that binds CD47 and CLDN18.2 to lessen or ameliorate the symptoms of every possible cancer.
For example, one of skill in the art is well-aware that cancer is difficult to prevent and treat. According to The Merck Manual of Diagnosis and Therapy, there are numerous molecular mechanisms which may drive cells to become cancerous, from genetic abnormalities to environmental factors. (The Merck Manuals Online Medical Library, [online]. Whitehouse Station, NJ: Merck Research Laboratories, 2006-2007. [retrieved on 10/19/2020]. Retrieved from the Internet: < URL: https://www.merckmanuals.com/professional/hematology-and-oncology/overview-of-cancer/cellular-and-molecular-basis-of-cancer >. Cellular and Molecular Basis of Cancer). However, the instant disclosure does not provide sufficient in vitro or in vivo evidence showing that the administration of a bispecific antibody which binds CD47 and CLDN18.2 can counter-act the cause or the manifestation of cancer as defined by The Merck Manual of Diagnosis and Therapy in order to ameliorate the disease.
Applicant's in vivo experiments (Example 5) describe a treatment for a cancer caused by injection of hCLDN18.2-NUGC-4 cells. Other experiments (Examples 3, 4, and 7) were performed ex vivo with cell culture. All of these experiments were performed with a cell line that overexpresses claudin 18.2 (i.e., CLDN18.2). However, according to Hong (Transl Cancer Res. 2020 May;9(5):3367-3374), not all cancers are positive for claudin 18.2.
Pharmaceutical therapies in the absence of in vivo clinical data are unpredictable for the following reasons; (1) the protein may be inactivated before producing an effect, i.e. such as proteolytic degradation, immunological inactivation or due to an inherently short half-life of the protein; (2) the protein may not reach the target area because, i.e. the protein may not be able to cross the mucosa or the protein may be adsorbed by fluids, cells and tissues where the protein has no effect; and (3) other functional properties, known or unknown, may make the protein unsuitable for in vivo therapeutic use, i.e. such as adverse side effects prohibitive to the use of such treatment. See page 1338, footnote 7 of Ex parte Aggarwal, 23 USPQ2d 1334 (PTO Bd. Pat App. & Inter. 1992).
There is insufficient guidance and direction as well as objective evidence provided for treating the scope of diseases encompassed by the claimed method. In view of the lack of predictability of the art (e.g., treating all cancers) to which the invention pertains, undue experimentation would be required to practice the claimed method of treating any cancer with a reasonable expectation of success, absent a specific and detailed description in Applicant's specification of how to effectively use the claimed agent and absent working examples providing evidence which is reasonably predictive that the claimed agent is effective for ameliorating any disease commensurate in scope with the claimed invention.
Reasonable correlation must exist between the scope of the claims and scope of the enablement set forth. In view of the quantity of experimentation necessary, the limited working examples, the nature of the invention, the state of the prior art, the unpredictability of the art and the breadth of the claims, it would take undue trials and errors to practice the claimed invention.
Applicant is invited to amend the claims to recite a cancer that expresses CLDN18.2 in order to address this issue.
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 2 and 14 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The claims recite preferential nested ranges of narrow and broader range within the same claim. For example, claim 2 recites ranges of "an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 10". Use of a narrow numerical range that falls within a broader range in the same claim may render the claim indefinite when the boundaries of the claim are not discernible. Description of examples and preferences is properly set forth in the specification rather than in a single claim. A narrower range or preferred embodiment may also be set forth in another independent claim or in a dependent claim. If stated in a single claim, examples and preferences lead to confusion over the intended scope of the claim. MPEP 2173.05(c)(I).
For the purpose of claim construction, the most permissive of the ranges is used to compare the claims to the prior art.
Claim 12 is 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 12 recites the term "preferably". Examples and preferences create confusion over the intended scope of a claim. It is not readily apparent if the preferred species recited are intended as limitations that narrow the scope of the claims. Description of examples or preferences is properly set forth in the specification rather than the claims. MPEP 2173.05(d).
For the purpose of claim construction, any limitation that is described as "preferably" in the claims is being considered optional.
Allowable Subject Matter
Claims 3-6 and 15-20 are 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 sequences have been searched and are found free of the art. The closest prior art is Liu (US20210230272A1). Liu teaches a bispecific antibody that binds to CLDN18.2 and CD47 (para. 0045-0047 and claim 11). However, Liu does not teach the claimed sequences.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PETER JOHANSEN whose telephone number is (571)272-0280. The examiner can normally be reached Monday-Friday, 6:00 to 2:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis can be reached at (571) 270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PETER JOHANSEN/Primary Examiner, Art Unit 1644
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