DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Claims 16-31 are pending. Claims 1-15 are canceled.
3. Claims 16-31 are under examination.
Priority
4. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
5. The information disclosure statements (IDS) submitted on 1/9/2024, 2/5/2024, 4/12/2024, 8/13/2024 and 11/20/2024 have been considered by the examiner.
Abstract
6. The abstract is objected to for referring to purported merits (e.g. novel).
Applicant is reminded of the proper content of an abstract of the disclosure.
A patent abstract is a concise statement of the technical disclosure of the patent and should include that which is new in the art to which the invention pertains. The abstract should not refer to purported merits or speculative applications of the invention and should not compare the invention with the prior art.
If the patent is of a basic nature, the entire technical disclosure may be new in the art, and the abstract should be directed to the entire disclosure. If the patent is in the nature of an improvement in an old apparatus, process, product, or composition, the abstract should include the technical disclosure of the improvement. The abstract should also mention by way of example any preferred modifications or alternatives.
Where applicable, the abstract should include the following: (1) if a machine or apparatus, its organization and operation; (2) if an article, its method of making; (3) if a chemical compound, its identity and use; (4) if a mixture, its ingredients; (5) if a process, the steps.
Extensive mechanical and design details of an apparatus should not be included in the abstract. The abstract should be in narrative form and generally limited to a single paragraph within the range of 50 to 150 words in length.
See MPEP § 608.01(b) for guidelines for the preparation of patent abstracts.
Objections
7. Claim 31 is objected to for reciting “in a method of treating cancer…the improvement comprising….”. A proper process claim should be in the following format: A method of …., comprising the steps: A, B and C.
Claim 31 recites the limitation "the improvement” in line 3. There is insufficient antecedent basis for this limitation in the claim.
Claim Rejections - 35 USC § 112
8. 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.
9. Claim 23 and 26 are 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.
Claims 23 and 26 depend from claim 16. Claim 16 requires the multispecific antigen-binding molecule to comprise a first antigen binding domain and a second antigen binding domain. The specification defines “antigen binding domain” as “an antibody portion which comprises a region that specifically binds and is complementary to the whole or a portion of an antigen” ([0018]). In general, antigen-binding domains contain both the antibody light chain variable region (VL) and antibody heavy chain variable region (VH) ([0018]) Claims 23 and 26 broaden the scope of the “antigen binding domain” to include any antibody variable fragments. Antibody variable fragments broadly encompass any fragments of a VH and/or VL, such as a single CDR, a VH alone, a VL alone. Therefore, claims 23 and 26 do not further limit claim 16.
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
10. 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.
11. Claims 26 and 27 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.
Claim 26 is rejected because the specification lacks adequate written description for a genus of antibody variable fragments that complete for binding to human RNF43 with a reference antibody defined in the claim.
Claim 27 is rejected because the specification lacks adequate written description for a genus of antigen binding domains that bind to the same human RNF43 epitope to which a reference antibody variable fragment (defined in the claim) binds.
“[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. Reagents 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.”)
Claim 26 recites “wherein the first antigen-binding domain comprises an antibody variable fragment that competes for binding to human RNF43 with any one of the antibody variable fragments of (a) to (e)”.
Claim 27 recites “wherein the first antigen-binding domain binds to the same human RNF43 epitope to which any one of the antibody variable fragments of (a) to (e) binds”.
The reference antibody (i.e. the antibody variable fragment of (a)-(e) of claims 26 and 27) is defined in the claims as comprising \6 CDRs of (a) antibody RNN0191kk, (b) antibody RNN0198oo, (c) antibody RNN0242nn, (d) antibody RNN0246jj or antibody RNN0275kk.
The specification (Example 8 and Fig. 6, reproduced below) discloses:
(i) no antibodies which compete for binding to RNF43 with RNN0207ii (Bin A).
(ii) RNN0187jj and RNN0192nn compete with each other for binding to RNF43 (Bin B);
(ii) no antibodies which compete for binding to RNF43 with antibody RNN0193jj (Bin C); and
(iv) RNNO242nn and RNNO246jj compete with each other for binding to RNF43 (Bin D).
PNG
media_image1.png
260
609
media_image1.png
Greyscale
PNG
media_image2.png
339
688
media_image2.png
Greyscale
Regarding part (a) of claims 26 and 27, the specification does not disclose any antibody that competes for binding to RNF43 with RNN0191kk, much less an antibody that binds to the same epitope to which RNN0191kk binds.
Regarding part (b) of claims 26 and 27, the specification does not disclose any antibody that competes for binding to RNF43 with RNN0198oo, much less an antibody that binds to the same epitope to which RNN0198oo binds.
Regarding part (c) of claims 26 and 27, the specification discloses one antibody RNNO246jj that competes for binding to RNF43 with RNN0242nn. The specification does not disclose an antibody that binds to the same epitope.
Regarding part (d) of claims 26 and 27, the specification discloses one antibody RNN0242nn that competes for binding to RNF43 with RNNO246jj. The specification does not disclose one antibody that binds to the same epitope.
Regarding part (e) of claims 26 and 27, the specification does not disclose any antibody that competes for binding to RNF43 with RNN0275kk, much less an antibody that binds to the same epitope to which RNN0275kk binds.
Therefore, for claim 26, the specification only discloses one antibody i.e. RNN0187jj for part (c) and one antibody i.e. RNN0192nn for part (d). For claim 27 the specification does not discloses any antibody.
Therefore the written description is not commensurate in scope with the claimed antibodies.
The interaction of the antibody binding domain with an antigen has been well characterized in the art. For example, Reis et al (Frontiers in Molecular Biosciences, 2022, 9: 945808) teaches that the paratope is the region of the Ab surface that is directly interacting with the corresponding antigen. It usually includes portions of both the light (L) and heavy (H) Ab chains. In particular, the paratope is often assumed to include all of the six CDRs, which are located in the variable domains VH and VL of the respective chains (see Figure 3A). The six CDRs are optimized by our immune system to generate high affinity paratopes for the molecular recognition of a specific target (page 5 under subheading 3.1). In the majority of paratopes (85%), we found the co-participation of framework (Fw) residues. This is an interesting aspect as their main role is to act as a scaffold for the CDRs. In fact, their contribution, while generally less important than that of the CDRs, can account for as much as 30% of the paratope (page 6, para 1). Reis et al. teaches that the epitope is the region of the Ag surface that is directly interacting with the Ab (see Figure 5A). The structural analysis of the antigens in our database shows that on average the epitope contains 14.6 ± 4.9 residues, thus it is similar in size to the paratope (page 7, column 2). Epitopes comprising only one linear amino acid sequence, often called sequential or linear epitopes, are rarely observed. Indeed, epitopes often are conformational, i.e., consisting of portions of the Ag that are discontinuous in sequence and become spatially close only upon folding (page 8, column 1). Abdiche et al. (PLOS ONE, 2017, 0169535) teaches antibodies targeting closely adjacent or minimally overlapping epitopes can displace one another (abstract). Abdiche et al. teaches that structural interpretation of these empiric cross-blocking results suggests that displacement occurs between mAbs that have minimal to no steric clashes or shared epitope contacts, reinforcing our proposed hypothesis of displacement occurring via a transient sandwich complex within which the mAbs kinetically perturb one another, resulting in the complex collapsing by expelling one mAb and retaining the other (page 14). These findings show that antibodies do not need to bind to the same epitope as another antibody to compete with the antibody for binding.
As shown by these prior art, the interaction of an antibody binding domain with antigen and identifying potential epitopes on proteins have been well characterized. However, the prior art does not teach how to predict the structural features of the antibodies that bind to a disclosed epitope. Thus, one still cannot predict the structural or functional features of plethora of antibodies that bind to a disclosed antigen or epitope, or compete with another antibody for binding to an epitope. These and other studies on antibody epitopes do not provide sufficient information for a skill artisan to predict the structural and functional properties of a genus of antibodies that bind to a particular antigen or epitope based on the disclosure of an antibody epitope or species of antibodies that bind to a particular epitope.
The specification fails to disclose a representative number of the species for the genus. The specification also fails to disclose a correlation between a structure and function (competes for binding to human RNF43 with any one of the antibody variable fragments of (a) to (e); or binding to the same epitope to which any one of the antibody variable fragments of (a) to (e) binds on human RNF43). Without further testing, one cannot identify which antibodies have the claimed function. 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.
Accordingly, the skilled artisan would not recognize that applicants were in possession of the invention as broadly claimed at the time the application was filed.
Claim Rejections - 35 USC § 102
12. 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.
13. Claim(s) 16, 18-21, 23-24 and 29-31 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Chen et al (WO2015/095392A1, pub. date: 6/25/2015, IDS filed on 1/9/2024).
Regarding claims 16, 20, 23 and 31, Chen et al. teaches a method of treating cancer in a subject comprising administering to the subject a bispecific antibody that binds to CD3 and a tumor antigen (page 318), wherein the tumor antigen is RNF43 (pages 82-83).
Regarding claims 18-19, because the bispecific antibody binds to CD3 (a T cell receptor), it would inherently have T cell-dependent cellular cytotoxicity.
Regarding claim 21, Chen et al. teaches that the bispecific antibody binds to CD3 epsilon (page 82, line 12).
Regarding claim 24, Chen et al teaches that the bispecific antibody comprises two Fab fragments (page 204, lines 37-39).
Regarding claim 29, Chen et al. teaches that the bispecific antibody comprises a human Fc domain having reduced Fc[Symbol font/0x67]R binding compared to a naturally occurring human Fc region (page 308, last para and page 390 1st para).
Regarding claim 30, Chen et al. teaches that the bispecific antibody binds to CD3 epsilon (page 82, line 12), and the bispecific antibody comprises a human Fc domain having reduced Fc[Symbol font/0x67]R binding compared to a naturally occurring human Fc region (page 308, last para and page 390 1st para).
Claim Rejections - 35 USC § 103
14. 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.
15. Claims 16-24 and 29-31 are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al (WO2015/095392A1, pub. date: 6/25/2015, IDS filed on 1/9/2024), in view of Boontanrart et al. (WO2015164392A2, pub. date 10/29/2015, IDS filed on 1/9/2024).
The teachings of Chen et al. have been discussed above as they apply to claims 16, 18-21, 23-24 and 29-31.
Regarding claim 17, Chen et al. does not teach treating gastric or colorectal cancer.
Regarding claim 22, Chen et al. does not teach that the bispecific antibody binds human RNF43.
Boontanrart et al. teaches that RNF43 has surprisingly been found to be a biological marker of a number of tumor types and this association may be exploited for the treatment of cancer (page 6, lines 20-21). Boontanrart teaches that GA (gastric cancer ) and CR (colorectal cancer) PDX (patient derived xenograft) tumor cell lines exhibited high RNF43 protein expression compared to normal tissue (Example 14 and Fig. 8 and example 16). Boontanrart teaches a method of treating cancer including colorectal cancer comprising administering to a subject having a cancer a pharmaceutical composition comprising a humanized antibody that binds to human RNF43 (page 4, claims 22-23).
Boontanrart teaches that the anti-RNF43 antibody can be a bispecific antibody that binds to human RNF43 and CD3 (page 2, line 26, and page 53, lines 11-14).
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 have used the RNF43/CD3 bispecific antibody to treat gastric or colorectal cancer in view of Boontanrart. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because Boontanrart teaches that GA (gastric cancer ) and CR (colorectal cancer) PDX (patient derived xenograft) tumor cell lines exhibited high RNF43 protein expression compared to normal tissue (Example 14 and Fig. 8 and example 16). 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 have used the RNF43/CD3 bispecific antibody which binds to human RNF43 to treat human colorectal cancer in view of Boontanrart. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because Boontanrart teaches that the anti-RNF43 antibody can be a bispecific antibody that binds to human RNF43 and CD3 (page 2, line 26, and page 53, lines 11-14).
16. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure: WO2016179003 (pub. date: 11/10/2016, IDS filed on 12/4/2019).
Conclusion
17. No claims are allowed. Claims 16-24, 26-27 and 29-31 are rejected. Claims 25 and 28 are objected to as being dependent from a rejected claim.
20. Any inquiry concerning this communication or earlier communications from the examiner should be directed to HONG SANG whose telephone number is (571)272-8145. The examiner can normally be reached Monday-Friday 8am-5pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gregory Emch can be reached on 571-272-8149. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/HONG SANG/Primary Examiner, Art Unit 1643
Prosecution Insights