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
2. Claims 1-10 are pending and currently under prosecution.
Priority
Applicant’s claim under 35 U.S.C. §§ 119(e) for benefit of the earlier filing date of application, is acknowledged.
Claim Rejections - 35 USC § 112
4. The following is a quotation 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.
5. The following is a quotation of 35 U.S.C. 112 (pre-AIA ), first paragraph:
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.
6. Claims 1-6 and 8-9 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventors, at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
MPEP § 2163 states that 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, 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. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 759 F.3d 1285, 111 USPQ2d 1780 (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 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. “Functional” terminology may be used “when the art has established a correlation between structure and function” but “merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing one has invented a genus and not just a species. Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 598 F3d 1336, 94 USPQ2d 1161, 1171 (Fed Cir. 2010).
1) 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/sites/default/files/documents/amgen_22feb2018.pdf. That Memorandum indicates that, in compliance with recent legal decisions, the disclosure of a full characterized antigen no longer is sufficient written description of an antibody to that antigen. Accordingly, the instant claims have been re-evaluated in view of that guidance.
Scope of the claimed genus
Claims 1-6 and 8-9 are drawn to a method comprising an antibody that binds to SEQ ID NO: 8, 9 10, 11, 12, or 13.
State of the Relevant Art
As summarized in the Specification, SEQ ID NO: 8, 9 10, 11, 12, or 13 are fragment of LANCL1; see [0020-0026] of the published application.
As was well-known in the antibody art, antibodies as a class share an overall structure generally comprising two heavy chain polypeptides that each comprises a heavy chain variable region (VH) and a heavy chain constant region made up of several domain (CH1, hinge, CH2, CH3, and for some antibodies, a CH4). Each of the heavy chains pairs with a light chain polypeptide that comprises a light chain variable region (VL) and a constant region. But while this overall structure is shared amongst antibodies from a wide variety of sources (human, rat, mouse, rabbit), the structure each antibody uses to bind its particular epitope on an antigen is structurally distinct and is formed by a recombination event that results in high variability at the amino acid sequence level. By the time the invention was made, it is well established in the art that the formation of an intact antigen-binding site in an antibody usually required the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three “complementarity determining regions” (“CDRs”) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro & Fransson, Frontiers in Bioscience 2008; 13:1619-33 (see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1). Chimeric antibodies comprise the heavy and light chain variable regions of a rodent antibody linked to human constant regions and preserve the entirety of the VH and VL of the parent antibody. Id. at 1619-20. Humanized antibodies comprise only the CDRs, or in some cases an abbreviated subset of residues within the CDRs, of a parental rodent antibody in the context of human framework sequences. Id. at Section 4. All of the CDRs of the heavy and light chain, in their proper order of CDR1, then 2, then 3, and in the context of framework sequences which maintain their required conformation are generally required to produce a humanized antibody in which the heavy and light chains associate to form an antigen-binding region that binds the same antigen as the parental rodent antibody. Id. at Section 4. Almagro provides a detailed discussion regarding various methods of humanization, including rationale design approaches and empirical approaches based on random screening. Almagro, Sections 4 and 5.
Examples of antigen binding domains comprising only a VH (or less commonly, a VL) that in turn comprise only three CDRs certainly do exist in the literature, but those antibodies generally comprise unique structures such as CDR1 and CDR3’s that are elongated in length and that are often disulfide linked. E.g., De Genst et al., Dev Comp Immunol 2006; 30:187-98. “Shuffling” of the VL (or less commonly the VH) had also been used to improve affinity of a parent antibody in certain instances. But the procedure generally required a "dominant" VH (i.e., a VH that is primarily responsible for antigen specificity). E.g., Yoshinaga et al., J. Biochem 2008; 143: 593-601.
Overall, at the time the invention was made, the level of skill for preparing antibodies and then selecting those antibodies with desired functional properties was high. However, even if a selection procedure 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 Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336 (Fed. Cir. 2010); see also Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1876 (Fed. Cir. 2011) (“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.”) Absent the conserved structure provided by all six CDRs of a parental antibody in the context of appropriate VH and VL framework sequences, the skilled artisan generally would not be able to visualize or otherwise predict, a priori, what an antibody with a particular set of functional properties would look like structurally.
Summary of Species disclosed in the original specification
Although the specification teaches Abnova H00010314-A01 antibody, Sigma-Aldrich HPA034994 antibody, a Novus Biologicals NBP1-81796 antibody; see [0025-000027]; however, the specification does not provide a representative number of species to which the claimed a genus of antibodies that binds to SEQ ID NO: 8, 9 10, 11, 12, or 13.
Are the disclosed species representative of the claimed genus?
MPEP § 2163 states that 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.
However, the specification does not provide a representative number of species to which the claimed a genus of antibodies that binds to SEQ ID NO: 8, 9 10, 11, 12, or 13.
Identifying characteristics and structure/function correlation
In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied 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. To meet this requirement in the instant case, the specification must describe structural features that convey the claimed binding activity, a prerequisite for utility in the recited composition.
As noted above, the art generally accepted that the combination of the CDRs within the VH and VL pair of an antibody were essential for binding specificity. But the specification does not describe what residues within the CDRs confer the binding activity claimed. Accordingly, the skilled artisan would not be able to discern a structure/function correlation for antibodies other than those comprising either all six CDRs (in the context of VH and VL regions) of one parental antibody, or the VH and VL of one parental antibody.
Further, the specification does not show that either the VH or the VL is “dominant” and could be paired with other VH or VL to form a new antibody that still bound the same antigen. It is again acknowledged that the skilled artisan possessed the methodology needed to “shuffle” the VL and/or VH and screen for binders. But that methodology did not allow the skilled artisan to visualize the structure of the alternate VH/VL chains prior to the step of screening. Accordingly, absent supporting evidence of a “dominant” VH or VL, the recitation of only a VH or only a VL does not provide a structure that the skilled artisan would consider to correlate with binding function.
For all of the reasons presented above, one of skill in the art would not know which of the countless other antibodies that meet the highly general structural requirements of the claims would also be able to bind SEQ ID NO: 8, 9 10, 11, 12, or 13. And none of the dependent claims provide sufficient additional structure or a structure/function correlation to provide an adequate written description of the genera claimed. Therefore, the skilled artisan would not reasonably conclude that the inventors, at the time the application was filed, had full possession of antibodies as broadly claimed. Given the lack of shared structural properties that provide the claimed binding activity, the limited number of species described, and the fact that the species that were described cannot be considered representative of the broad genus, Applicant was not in possession of the invention as claimed.
2) Turning to another issue, the claim 1 is directed to a sequence having at least 80% sequence identity to SEQ ID NO: 8, 9 10, or 11, 12, 13. Thus, the claim is drawn to a genus of sequences having at least 80% sequence identity to SEQ ID NO: 8, 9 10, or 11, 12, 13.
The specification teaches SEQ ID NO: 8, 9 10, or 11, 12, 13; see [0020-0026] of the published application. The specification does not teach that a sequence having at least 80% sequence identity to SEQ ID NO: 8, 9 10, or 11, 12, 13 would have or retain the activity or function of SEQ ID NO: 8, 9 10, or 11, 12, 13.
Given the fact that the claims are drawn to a genus of sequences having at least 80% sequence identity to SEQ ID NO: 8, 9 10, or 11, 12, 13, which have no particular function or activity, there is no correlation between any one particularly identifying structural feature and any one particularly identifying functional feature. Consequently, it is submitted that the skilled artisan could not immediately envision, recognize or distinguish at least a substantial number of the genus of sequences having at least 80% sequence identity to SEQ ID NO: 8, 9 10, or 11, 12, 13 to which the claim is directed.
Although the specification teaches SEQ ID NO: 8, 9 10, or 11, 12, 13; SEQ ID NO: 8, 9 10, or 11, 12, 13 is not reasonably representative of the genus of sequences having at least 80% sequence identity to SEQ ID NO: 8, 9 10, or 11, 12, 13. This is largely because each sequence that has at least 80% sequence identity to SEQ ID NO: 8, 9 10, or 11, 12, 13 has substantially varying structure and need not have any particular function or activity.
Guidelines states, “[p]ossession may be shown in a variety of ways including description of an actual reduction to practice, or by showing the invention was ‘ready for patenting’ such as by disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention” (Id. at 1104). “Guidelines” further states, “[f]or inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus” (Id. at 1106); accordingly, it follows that an adequate written description of a genus cannot be achieved in the absence of a disclosure of at least one species within the genus. Moreover, because the claim encompasses a genus of sequences having at least 80% sequence identity to SEQ ID NO: 8, 9 10, or 11, 12, 13, which vary both structurally and functionally, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. In this instance, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; Applicant has not shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; and Applicant has not described distinguishing identifying characteristics sufficient to show that Applicant was in possession of the claimed invention at the time the application was filed.
Thus, it is submitted that the instant claims, and the disclosure describing the claimed subject matter, fails to satisfy the written description requirement set forth under 35 U.S.C. § 112, first paragraph.
7. 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.
Claim Rejections - 35 USC § 103
8. 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 of this title, 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.
9. The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
10. Claims 1-2 and 4-10 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (Cell Death and Disease (2018) 9:197, pages 1-12, IDS) in view of Novus Biologicals NBP1-81796 antibody (9/28/2019, pages 1-4) evidenced by product datasheet of NBP1-81796 (2/21/2025, pages 1-4).
Claims 1-2 and 4-10 are herein drawn to a method of inhibiting cancer cell proliferation in a subject, comprising administering to the subject an antibody that specifically binds to LANCL1, wherein the antibody binds to SEQ ID NO: 12.
Wang et al. teach that LanCL1 promotes prostate cancer cell proliferation and helps protect prostate cancer cells from damage caused by oxidative stress; and suppression of LanCL1 by siRNA results in increased cancer cell apoptosis; see entire document, e.g., abstract, Figure 1. Wang et al. teach that that LanCL1 could be a novel therapeutic target for improving the efficiency of treating prostate cancer; see bridging paragraph of pages 1-2. Wang et al. teach anti-LANCL1 antibody and the antibody is labeled with streptavidin-biotin-peroxidase; see right col. of page 2, 5th paragraph of left col. on page 3, Figure 6.
Although Wang et al. teach anti-LANCL1 antibody, Wang et al. do not teach immunogen of the anti-LANCL1 antibody and treating prostate cancer using an anti-LANCL1 antibody.
However, these deficiencies are remedied by Novus Biologicals NBP1-81796 antibody evidenced by product datasheet of NBP1-81796.
Immunogen of Novus Biologicals NBP1-81796 antibody is the same as the instant claimed SEQ ID NO: 12, NBP1-81796 is a polyclonal antibody; see entire document and page 1 of product datasheet of NBP1-81796.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of the references so as to treat cancer using NBP1-81796 anti-LANCL1 antibody. One would have been motivated to do so because Wang et al. teach that LanCL1 promotes prostate cancer cell proliferation and helps protect prostate cancer cells from damage caused by oxidative stress, suppression of LanCL1 by siRNA results in increased cancer cell apoptosis, and LanCL1 could be a novel therapeutic target for improving the efficiency of treating prostate cancer; Novus Biologicals NBP1-81796 antibody evidenced by product datasheet of NBP1-81796 teach that immunogen of Novus Biologicals NBP1-81796 antibody is the same as the instant claimed SEQ ID NO: 12. Thus, one of ordinary skill in the art would have a reasonable expectation of success that by combining the teachings of the references so as to treat cancer using NBP1-81796 anti-LANCL1 antibody to arrive the instant claimed invention, because LanCL1 could be a novel therapeutic target for improving the efficiency of treating prostate cancer as taught by Wang et al.
Conclusion
11. No claim is allowed.
12. Any inquiry concerning this communication or earlier communications from the examiner should be directed to YAN XIAO whose telephone number is (571)270-3578. The examiner can normally be reached M-F 8-5 EST.
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/YAN XIAO/Primary Examiner, Art Unit 1642