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 .
DETAILED ACTION
Claims 20-43 are pending.
Claims 20-43 are under examination on the merits.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Claims 20-43 have an effective filing date of 08/02/2019, corresponding to U.S. App. No. 16/530,006.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 08/29/2023 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Objection to the Drawings
The drawings are objected to, because the sequence information in Figures 1 and 2 is blurry and difficult to read. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Objection to the Claims
Claim 36 recites the term “CLDN18-2-positive,” which appears to be a typographical error that was intended to read “CLDN18.2-positive.”
Claim Rejections
35 U.S.C. 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.
Claim 36 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 36 recites various types of CLDN18.2-positive human cells, including CHO-CLDN18.2 cells. CHO cells are derived from Chinese hamster ovaries, and are therefore not human cells.
Applicant is informed that one means of overcoming the instant rejection of the claims under 35 U.S.C. 112(b) is to amend claim 36 to remove the recitation of CHO-CLDN18.2 cells.
35 U.S.C. 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.
Claims 37-43 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. Claim 13 is drawn to a method of treating a subject suffering from a CLDN18.2-expressing disease or neoplasm, such as cancer. Page 78 of the specification states that “[t]he term ‘treatment’ refers to both therapeutic treatment and prophylactic or preventative measures (emphasis added).” As such claim 13 encompasses the treatment, as well as the prevention of cancer. Although the specification is enabled for treating cancer by administering an anti-CLDN18.2 x anti-CD3 bispecific antibody to a subject in need thereof, the specification is not enabled for preventing cancer by administering an anti-CLDN18.2 x anti-CD3 bispecific antibody to a subject in need thereof. 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.
MPEP § 2164.01 states:
The standard for determining whether the specification meets the enablement requirement was cast in the Supreme Court decision of Mineral Separation v. Hyde, 242 U.S. 261, 270 (1916) which postured the question: is the experimentation needed to practice the invention undue or unreasonable? That standard is still the one to be applied. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). Accordingly, even though the statute does not use the term “undue experimentation,” it has been interpreted to require that the claimed invention be enabled so that any person skilled in the art can make and use the invention without undue experimentation. In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404 (Fed. Cir. 1988).
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.” These factors include but are not limited to:
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The breadth of the claims;
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The nature of the invention;
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The state of the prior art;
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The level of one of ordinary skill;
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The level of predictability in the art;
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The amount of direction provided by the inventor;
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The existence of working examples; and
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The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). The factors most relevant to this rejection are 1) the amount of direction provided by the inventor and 2) the existence of working examples. In the instant case, the amount of direction provided by the inventor and existence of working examples disclosed in the specification, as filed, would not be sufficient to enable the skilled artisan to make and/or use the claimed invention at the time the application was filed without undue experimentation.
(1) The amount of direction provided by the inventor - The amount of guidance or direction needed to enable an invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The “amount of guidance or direction” refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling. See, e.g., Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1326 (Fed. Cir. 2004). Due to the high level of unpredictability in the area of disease prevention, particularly cancer prevention, the skilled artisan would need significant guidance in preventing cancer by practicing the claimed method. The skilled artisan recognizes that keeping individuals free of cancer indefinitely is an intractable proposition, if not now wholly impossible, given, for example, that cancers are widely heterogeneous diseases, having widely varying pathologies and etiologies, and with causes that are multifactorial and as yet only partially characterized and poorly understood. It is generally recognized that a disease cannot be prevented unless and until its causes are fully appreciated and understood to a degree that it becomes possible to intercede effectively to block its onset or development by any cause.
(2) The existence of working examples – The examples of the specification demonstrate methods that may be used to treat cancer by administering an anti-CLDN18.2 x anti-CD3 bispecific antibody to a subject in need thereof; however there is no showing in the specification of any means by which one skilled in the art could prevent cancer by administering an anti-CLDN18.2 x anti-CD3 bispecific antibody to a subject in need thereof. Therefore one skilled in the art would be subject to undue experimentation to practice the instant invention as it is currently claimed.
In conclusion upon careful consideration of the Wands factors that are used to determine whether undue experimentation is required to practice an invention, the amount of direction provided by the inventor and the working examples provided, as filed, is not deemed sufficient to enable the skilled artisan to make and/or use the invention commensurate in scope with the instant claims at the time the application was filed without undue experimentation.
Applicant is informed that one means of overcoming the instant rejection of the claims under 35 U.S.C. 112(a) is to amend the specification such that the definition of “treatment” does not encompass the word “prevention.”
Claims 20-43 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The purpose of the written description requirement is to ensure that the inventor had possession, at the time the invention was made, of the specific subject matter claimed. To satisfy the written description requirement, a patent 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. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.
Claims 20 and 37 are drawn to methods of inducing cytotoxicity in a cell expressing Claudin 18.2 (CLDN18.2) and treating a subject suffering from a CLDN18.2-expressing disease or neoplasm, and both methods require an anti-CLDN18.2 x anti-CD3 bispecific antibody that has a half maximal effective concentration (EC50) of ˂ 300 pM, as measured in a cell-based viability assay comprising combining CLDN18.2-positive human cells and human T cells, at a ratio of about 1:10, respectively. The claims encompass a large genus of molecules that includes any anti-CLDN18.2 x anti-CD3 bispecific antibody that has an EC50 of ˂ 300 pM, as measured in a cell-based viability assay comprising combining CLDN18.2-positive human cells and human T cells; however following a review of the specification, it appears that three anti-CLDN18.2 x anti-CD3 bispecific antibodies that have an EC50 of ˂ 300 pM, as measured in a cell-based viability assay comprising combining CLDN18.2-positive human cells and human T cells, have been described: 1) CL-1 x I2C-6His (SEQ ID NO: 131) demonstrates an EC50 of ˂ 300 pM by combining CLDN18.2-positive human cells (SNU-601, SNU-620, GSU, IM95, and NUGC4; which are CLDN18.2-expressing human gastric cells) and human T cells (PBMC); 2) CL-1 x I2C-scFc (SEQ ID NO: 132) demonstrates an EC50 of ˂ 300 pM by combining CLDN18.2-positive human cells (SNU-601, SNU-620, GSU, IM95, and NUGC4; which are CLDN18.2-expressing human gastric cells) and human T cells (PBMC); and 3) CL-2 x I2C-scFc (SEQ ID NO: 144) demonstrates an EC50 of ˂ 300 pM by combining CLDN18.2-positive human cells (SNU-601, SNU-620, GSU, IM95, and NUGC4; which are CLDN18.2-expressing human gastric cells) and human T cells (PBMC). See Tables 4 and 5 of the specification. Even though Applicant has disclosed three species within the claimed genus, the specification does not provide adequate written description for the entire claimed genus, because one skilled in the art would be unable to immediately envision, recognize, or distinguish at least most of the members comprised within the genus claimed, specifically, which anti-CLDN18.2 x anti-CD3 bispecific antibodies display an EC50 of ˂ 300 pM, as measured in a cell-based viability assay comprising combining CLDN18.2-positive human cells and human T cells. As detailed below Applicant’s disclosure is not sufficient to demonstrate possession of the entire claimed genus, and as such Applicant’s disclosure does not satisfy the written description requirement of 35 U.S.C. 112(a).
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
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A “representative number of species” means that the species which are adequately described are representative of the entire 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. In the instant case, Applicant has disclosed three species within the genus claimed; however given the substantial antibody structure variation within the claimed genus, as well as the high level of unpredictability in the art, the disclosure of three species comprised within the claimed genus is not sufficiently representative of the entire genus.
Furthermore Applicant has not disclosed relevant, identifying characteristics of anti-CLDN18.2 x anti-CD3 bispecific antibodies that display an EC50 of ˂ 300 pM, as measured in a cell-based viability assay comprising combining CLDN18.2-positive human cells and human T cells, because the instant specification does not provide structural antibody features that correlate with a functional ability to display an EC50 of ˂ 300 pM, as measured in a cell-based viability assay comprising combining CLDN18.2-positive human cells and human T cells. It is well-known in the art that different antibodies specific for the same antigen will display markedly different EC50 values. For example at Table 7 (p. 31), Li et al. (US PG PUB 2006/0127393, publication date: 06/15/2006) teach that different clones of antibodies specific for the same antigen (DKK-1) will display markedly different EC50 values as measured in a cell-based viability assay using the same cell type (ST2 cells). In viability assays using mouse DKK-1, anti-DKK-1 antibody clone 5H6-1 displayed an EC50 value of 2068 nM compared to an EC50 value of 272 nM for anti-DKK-1 antibody clone 10A7-1. In viability assays using human DKK-1, anti-DKK-1 antibody clone 7D6-1 displayed an EC50 value of 1465 nM compared to an EC50 value of 63 nM for anti-DKK-1 antibody clone 10A7-3. Therefore absent a description of the at least minimal structural features correlating with a functional ability to display an EC50 of ˂ 300 pM, as measured in a cell-based viability assay comprising combining CLDN18.2-positive human cells and human T cells, which are shared by members of a genus commonly sharing this function, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish which anti-CLDN18.2 and which anti-CD3 heavy and light chain amino acid sequences (or combinations thereof) may be combined such that a resultant CLDN18.2 x anti-CD3 bispecific antibody displays an EC50 of ˂ 300 pM, as measured in a cell-based viability assay comprising combining CLDN18.2-positive human cells and human T cells.
Although screening techniques can be used to isolate CLDN18.2 x anti-CD3 bispecific antibodies that display an EC50 of ˂ 300 pM, as measured in a cell-based viability assay comprising combining CLDN18.2-positive human cells and human T cells, Applicant is reminded that the written description requirement of 35 U.S.C. 112 is severable from the enablement provision. As stated in Vas-Cath Inc. v. Mahurkar (CA FC) 19 USPQ2d 1111, 935 F2d 1555, “The purpose of the ‘written description’ requirement is broader than to merely explain how to ‘make and use’; the applicant must also convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.”
Accordingly given the lack of particularity with which the claimed CLDN18.2 x anti-CD3 bispecific antibodies are described in the specification, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish at least most of the members of the genus to which the claims are directed, and therefore the specification would not reasonably convey to the skilled artisan that Applicant was in possession of the claimed invention at the time the application was filed.
It is further noted that claim 21 is drawn to a human antibody; however following a review of the specification, it appears that the CLDN18.2 x anti-CD3 bispecific antibodies that have been prepared are murine antibodies. The Federal Circuit in Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875, 1877-78 (Fed. Cir. 2011) has found that possession of an antibody having mouse heavy and light chain variable regions provides a structural “stepping stone” to the corresponding chimeric antibody, but not to human antibodies. Therefore given that possession of murine antibodies does not demonstrate possession of human antibodies, the human antibody as recited in claim 20 is rejected under 35 U.S.C. 112(a).
Applicant is informed that one means of overcoming the instant rejection of the claims under 35 U.S.C. 112(a) is to 1) amend claim 20 to specify that the bispecific antibody construct comprising a first domain which binds to human CLDN18.2 and a second domain which binds to CD3 further comprises the amino acid sequence of SEQ ID NO: 131, 132, and 144, as these CLDN18.2 x anti-CD3 bispecific antibodies have been shown to display an EC50 of ˂ 300 pM, as measured in a cell-based viability assay comprising combining various CLDN18.2-positive human cell lines and human T cells, and 2) either remove the recitation of human antibodies from claim 21 or demonstrate that Applicant has prepared human CLDN18.2 x anti-CD3 bispecific antibodies.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NELSON B MOSELEY II whose telephone number is (571)272-6221. The examiner can normally be reached on M-F, 9:00-6:00 EST.
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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/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642