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 .
Election/Restrictions
Applicant’s election without traverse of new Group 1.2, wherein the antibody has the heavy and light chain variable region CDR1-3 of SEQ ID NO:52-54 and 56-58, respectively, and species of drug which is a topoisomerase inhibitor in the reply filed on 2/2/2026 is acknowledged.
Alternative Names
SEZ6L2 is also known as Seizure Related 6 Homolog Like 2, Seizure 6-like 2 and PSK.
Specification
The disclosure is objected to because of the following informalities: In Example 4, second paragraph, second sentence (p. 96, line 15), “Two mice were fused after four weeks,..” does not make sense.
Appropriate correction is required.
The use of the term ForteBio (p. 101, lines 4, 5 and 9), which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
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 9 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 1, upon which claim 9 depends, already requires the antibody, or antigen binding fragment thereof, “does not bind SEZ6 or SEZ6L” Because claim 9 recites only the same limitation, it is not further limiting. 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)
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.
Claim 1, 6-9, 11-13, 18, 21 and 65 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.
Independent claim 1 is drawn to an anti-human SEZ6L2 antibody, or antigen binding portion thereof, that a) inhibits tumor growth in an in vivo human small-cell lung carcinoma (SCLC) xenograft assay with a tumor growth inhibition % (TGI%) at least about 50% relative to a human IgG antibody which is not specific for SEZ6L2 and which is administered at the same dose and frequence as the SEZ6L2 antibody, or antigen binding portion thereof, and b) does not bind SEZ6 or SEZ6L. The antibody of claim 1 has no recited structure.
Dependent claim 8 is drawn to an antibody, or antigen binding fragment thereof, that binds the same epitope as the antibody of claim 1. No epitope to which one of the disclosed anti-human SEZ6L2 antibodies binds is disclosed. The immunogen was the whole extracellular portion of the human SEZ6L2 protein (p. 85, lines 20-22, and p. 96, line 9, 816 amino acids in length). As supported by the prior art, there would reasonably be expected to be multiple epitopes contained in the extracellular domain. Also, there can be significant antibody diversity for the same epitope, thereby resulting in the inability of the skilled artisan to immediately envisage a representative number of antibody species to support the description of the genus of antibodies claimed in claim 1 and most dependent claims and particularly claim 8.
Two and a half decades before the instant invention, Andria et al. (J. Immunol. 144(7):2613-2619, 1990, Abstract) examined the variable region of antibodies binding the same decapeptide and found, “These analyses revealed that a wide range of different V regions are capable of binding with the same decapeptide epitope, and that these antibody sequence differences generally coincided with different binding fine specificities.” Andria et al. also note (p. 2617 col. 1, second paragraph), “Diversity between antibodies produced against a single epitope was predicted by Wu and Kabat (35) when they wrote ". . . it should be borne in mind that the contour of an antibody site having a given specificity or binding affinity for a given determinant could conceivably be formed by several kinds of patterns of amino acid sequence." The diversity of decapeptide-specific antibodies confirms their prediction, and it reveals a redundancy in the potential of the immune system to respond against Ag.” Later, Nair et al. (J. Immunol. 168:2371-2382, 2002, p. 2371, beginning of col. 2) identified three distinct antibodies that recognized the same epitope, a peptide antigen, yet have different structures both within and outside the CDRs (Fig. 1). As stated under the Discussion heading on p. 2378, “Diverse Abs exhibit equivalent topologies while recognizing a common immunodominant peptide epitope in similar conformation”. More recently, Ferrara et al. (mAbs 7(1):32-42, 2015) looked at polyclonal antibodies but the logic can be extended to structures of potential monoclonal antibodies therefrom. In looking for ubiquitin binding antibodies from yeast display and then phage selection, 58 unique HCDR3 (heavy chain variable region CDR3) clusters were found and a total of 107 different HCDR3s were identified (p. 34, col. 1, second paragraph). Ferrara et al. used an antibody library with diversity of over 3 x 1011 for initial antigen panning, finding that 105 to 106 antibodies had some reactivity to the antigen (col. 2, p. 36, third paragraph). Deep sequences of polyclonals recognizing the same antigen using the highest stringency parameters showed that the number of unique HCDR3s ranged from 74 to 460 (p. 36, col. 2, third paragraph, noting that deep sequencing was only performed on HCDR3s). Additionally, it is mentioned (p. 32, col. 2) that the ERBB protein has over 1,200 commercially available antibodies, though there may be overlap of antibodies within that group. Ferrara et al. showed not only that there can be significant structural diversity of antibodies binding the same antigen, but also that one antigen can have multiple epitopes (Fig. S1, green, also p. 36, col. 2, second paragraph). Wong et al. (MABS, 13(1):e1873478, 8 pages, 2021) discusses that most antibodies binding the same epitope have similar sequences, however, there are antibodies that do so and have different HCDR3 sequences and lengths. Using computer modeling, they identified 920 unique antibodies binding the same epitope (p. 2, col. 2, second paragraph and Table 1). This includes 435 antibodies with highly similar HCDR3s and 266 with low HCDR3 similarity (p. 3, col. 1, first and second full paragraphs). These references support the lack of written description for the genus of antibodies encompassed by claim 1 and dependent claims, with the exception of claims 6 and 7.
While in the instant application murine anti-SEZ6L2 antibodies were made by immunizing mice (Example 2), only the variable region sequences of four antibodies are disclosed (mu16H8, mu3E2, mu20C4 and mu2E4, Example 3). Each was humanized by grafting into human framework regions with some additional framework mutations required to maintain favorable properties (Example 3 and Tables 5-6). To make human antibodies, transgenic mice were immunized and produced 16 antibodies (Example 4 and Table 10). Human antibodies 1A1, 1C6, 3A1, 3A2, 3A3, 3B1, 3B3, 3B6 and murine antibodies 16H3, 3E2, 2E4 and 20C4 and corresponding humanized antibodies did not bind SEZ6 or SEZ6L (Example 10, Figs. 5A-5L; section b) of claim 1); however, there is no information on the specificity of the other 8 human antibodies not addressed in Example 10. Only the above 8 human and 4 murine/humanized anti-human SEZ6L2 antibodies meet the limitations of claim 1, section b). None, however, meet the limitations of section a) of claim 1. The antibody, or antigen binding portion thereof, of claims 6 and 7 have sufficient structural description supported by the specification to meet the binding limitations of claim 1, but they do not meet the tumor growth inhibition limitation of the claim (section a).
There is no disclosure of any anti-SEZ6L2 antibody, or antigen binding portion thereof, which alone inhibits tumor growth. Even assuming there was written description to support the genus of anti-human SEZ6L2 antibodies meeting the limitations of claim 1, section b), which it is not agreed there is, there is no disclosure of such an antibody meeting the limitation of section a) of claim 1. The only working example of tumor inhibition required antibody-cytotoxic drug conjugates. Example 5 concludes, “Not only do these results demonstrate that exemplary SEZ6L2 antibodies described herein are able to bind SEZ6L2 antigen on the cell surface and facilitate the delivery of a cytotoxic payload resulting in cell death, but the above data also demonstrate that multiple anti-SEZ6L2 antibodies can mediate killing of SCLC tumor cells.” This mediated tumor cell killing is only by means of allowing a cytotoxic payload to be internalized, saporin toxin in the case of Example 5. Similarly, Example 6 used the tubulin inhibitor monomethyl auristatin E (MMAE) conjugated to one of the anti-SEZ6L2 antibodies to show it reduced tumor mass in vivo in a mouse xenograft model. This also involves internalization of the inhibitor. Similarly, Example 8 describes a conjugate of the anti-SEZ6L2 antibody with PBD (pyrrolobenzodiazepine), which is internalized and induces SCLC and prostate cell death in vitro, but does so immunospecifically in response to SEZ6L2 binding and internalization. The antibody drug conjugate (ADC) was used in vivo in athymic mice to treat SCLC (Example 9), wherein the drug was MMAE. Finally, Example 11 showed in vitro that when an anti-SEZ6L2 antibody ADC was combined with a PARP inhibitor, in enhanced the reduction in viable cancer cells. No wherein is the antibody alone shown to inhibit tumor growth. Therefore, it does not appear the inventors were in possession of an anti-human SEZ6L2 antibody as set forth in claim 1 that meets the limitations related to tumor growth inhibition in section a) of the claim. Because claim 12 is drawn to the antibody, or antigen binding portion thereof, of claim 1 conjugated to a least one drug, but does not specify the drug, e.g., that it is cytotoxic, the conjugate of claim 12 does not necessarily fulfill the functional limitation of claim 1. While the elected species of drug for claim 13, a topoisomerase inhibitor, meets the limitation for a conjugated drug that would reasonably be expected to inhibit tumor growth as set forth in claim 1 when conjugated to any of the 4 humanized or 16 human anti-human SEZ6L2 antibodies disclosed, the other drugs listed do not necessarily. For example, neither a hormone agent nor a nucleic acid for gene therapy would necessarily be reasonably expected by the skilled artisan to function in an ADC to induce death of tumor cells to the extent set forth in claim 1.
It is stated in AbbVie Deustschland GmbH v. Janssen Biotechnology, Ltd., 111 USPQ 1780, 1789 (759 F.3d 1285, 1298), (Fed. Cir. 2014) discussing Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005) that “When a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed results and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus." Again in AbbVie at 1788, reiterating Enzo Biochem., Inc., 323 F.3d at 964, “It is true that functionally defined claims can meet the written description requirement if a reasonable structure-function correlation is established, whether by the inventor as described in the specification or known in the art at the time of the filing date…” As to the antibody, aside from the disclosed anti-human SEZ6L2 antibodies (4 murine and humanized version thereof and 16 human), there is no generalizable structure-function correlation to support the full genus of encompassed antibodies binding human SEZ6L2 and, more specifically, which do not bind SEZ6 or SEDZ6L, including those binding the same epitope (none of which are identified).
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), clearly states that “applicant must 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.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
With the exception of the disclosed 8 human and 4 murine/humanized antibodies or antigen binding portions thereof (human antibodies 1A1, 1C6, 3A1, 3A2, 3A3, 3B1, 3B3, 3B6 and murine antibodies 16H3, 3E2, 2E4 and 20C4 and corresponding humanized antibodies; see Tables 6 and 9) that have the required binding specificity as discussed above, the skilled artisan cannot envision the detailed chemical structure of the encompassed antibodies which bind human SEZ6L2 and do not bind SEZ6 or SEZ6L, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Also, the skilled artisan cannot envision any antibodies which are not unconjugated to a cytotoxic drug and that meet the functional limitations of claim 1, section a). Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The antibody or ADC itself, in this instance, is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991).
Therefore, only an ADC wherein the antibody is human antibody 1A1, 1C6, 3A1, 3A2, 3A3, 3B1, 3B3, 3B6 or murine antibodies 16H3, 3E2, 2E4 and 20C4 or corresponding humanized antibodies, or an antigen binding portion thereof, or wherein the antibody comprises the variable heavy and light chain variable region CDR1-3 thereof, and wherein the conjugated drug is a cytotoxic drug, but not the full breadth of the claim meets the written description provision of 35 U.S.C. § 112(a). Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115).
Prior Art
The prior art made of record and not relied upon is considered pertinent to Applicant's disclosure.
US Patent 9,993,566 B2 and 9,678,987 B2 (both cited in the IDS filed 7/15/2023) teach antibodies that bind SEZ6L2, identified by a dagger symbol in Tables 5 and 3, respectively. Example 17 and 18, respectively, of both patents teach conjugation of an anti-SEZ6 antibody to a toxin, wherein the antibody mediates internalization of the toxin into and cell killing of primary tumors in vitro and in vivo in an orthotopic NTX tumor mouse model. These antibodies do not share the variable heavy and light chain CDR1-3 of the claimed antibody.
US 2012/0122126A1 teaches antibodies that bind PSK, however, they do not share the variable heavy and light chain CDR1-3 of the claimed antibody.
WO 2007116923 A2 teaches SEZ6L2 siRNA. It indicates that strong SEZ6L2 expression may be a prognostic indicator of lung cancers (Example 3). However, treatment of non-small cell lung cancer cells in vitro with siRNA reducing expression of SEZ6L2 did not inhibit the cancer cell growth, “suggesting that up-regulation of SEZ6L2 is not directly related to growth or survival of cancer cells.” (Example 4). This supports the lack of expectation of an anti-SEZ6L2 antibody alone, i.e., in the absence of a cytotoxic payload, having antitumor activity.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Claire Kaufman, whose telephone number is (571) 272-0873. Examiner Kaufman can generally be reached Monday through Friday 7am-3:30pm, Eastern Time.
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Claire Kaufman
/Claire Kaufman/
Primary Examiner, Art Unit 1674
June 3, 2026
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