DETAILED ACTION
Notice of Pre-AIA or AIA Status
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. This action is in response to the papers filed July 29, 2026. Applicant’s remarks and amendments have been fully and carefully considered but are not found to be sufficient to put the application in condition for allowance. Any new grounds of rejection presented in this Office Action are necessitated by Applicant's amendments. Any rejections or objections not reiterated herein have been withdrawn. This action is made FINAL.
Applicants’ election without traverse of Group I in the reply filed on February 20, 2026 is reiterated for the record. Additionally, Applicants elected DLL3-targeted therapy (Species I) and cg20728514 (Species II). It is noted that cg20728514 appears in Tables 1-3 in the Specification.
Claims 1, 44, 54, 56, 229, 433, 443, 449, 460, 470, and 483-484 are currently pending.
Claims 229, 433, 443, 449, 460, and 470 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected subject matter (either a nonelected invention or nonelected species), there being no allowable generic or linking claim. Election was made without traverse in the reply filed on February 20, 2026.
Applicants are reminded that for any amendment being filed in response to a restriction or election of species requirement and any subsequent amendment, any claims which are non-elected must have the status identifier (withdrawn). In response to this Office Action, Claim 443 should be indicated as withdrawn.
The claims have been examined to the extent that the claims read on the elected therapy (DLL3-targeted therapy) and the elected methylation site (cg20728514). The additionally recited therapies and methylation sites have been withdrawn from consideration as being directed to nonelected subject matter. Prior to allowance of the claim, any nonelected subject matter that is not rejoined with any allowed elected subject matter will be required to be removed from the claims.
Claim Rejections - 35 USC § 112(b)
3. 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 1, 44, 54, 56, and 483-484 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.
Claims 1, 44, 54, 56, and 483-484 are objected to for referring to specific figures and/or tables in the specification. MPEP 2173.05(s) states that “Where possible claims are to be complete in themselves. Incorporation by reference to a specific figure or table “is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into a claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.”
Response To Arguments
4. In the response the Applicants traversed the rejection under 35 USC 112(b). The Applicants argue that exceptional circumstances are present because each of the recited Tables contains hundreds of specific CpG methylation site identifiers (cg207285 14), each with associated genomic coordinates (e.g., chr22:44568423) and gene annotations (e.g., PARVG.TSS1500). These identifiers are standardized designations from the Illumina methylation array platform and cannot practically be reduced to prose claim language. The sheer number of methylation sites (the Tables collectively contain thousands of specific genomic coordinates) makes incorporation by reference the only practical means of defining the claimed methylation panels.
This argument has been fully considered but is not persuasive. The Applicants have not met the burden of establishing there is no practical way to define the invention in words. Methylation sites are commonly referred to in claims by their Illumina identification numbers. The rejection is maintained.
Claim Rejections - 35 USC § 112(a)
5. 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, 44, 54, 56, and 484 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.
The instant claims encompass treating a subject for small cell lung cancer (SCLC) by administering a DLL3-targeted therapy. The claims do not define the DLL3-targeted therapies in terms of their complete structure or any other relevant identifying characteristics. The claimed DLL3-targeted therapy can be an antibody, protein, peptide, small molecule, an inhibitory RNA molecule (e.g., siRNA, shRNA, ribozymes, and antisense oligonucleotides), a vaccine, or a pharmaceutical.
The specification (para 0082 of the PG-PUB) teaches the following:
In some embodiments, the subject is administered a DLL3-targeted therapeutic. A DLL3-targeted therapeutic, as used herein, describes any agent, molecule, or compound capable of binding to a DLL3 protein and having therapeutic properties in treating cancer, including small cell lung cancer such as SCLC-A. In some embodiments, the DLL3-targeted therapeutic is an anti-DLL3 antibody or fragment thereof. In some embodiments, the DLL3-targeted therapeutic is rovalpituzumab. In some embodiments, the DLL3-targeted therapeutic is an antibody-drug conjugate. In some embodiments, the DLL3-targeted therapeutic is rovalpituzumab tesirine. In some embodiments, the DLL3-targeted therapeutic is a DLL3-targeted cellular therapy. DLL3-targeted cellular therapies include any cell-based therapeutic capable of binding to DLL3. A DLL3-targeted therapeutic may be an immune cell capable of targeting DLL3-expressing cells, for example, via expression of a DLL3-binding agent such as a DLL3-targeted chimeric antigen receptor (CAR) or T cell receptor (TCR). In some embodiments, the DLL3-targeted cellular therapy is a DLL3-targeted CAR T cell. In some embodiments, the DLL3-targeted cellular therapy is a DLL3-targeted CAR NK cell.
The specification discloses a single particular DLL3-targeted therapeutic (namely rovalpituzumab). The disclosure of a single particular DLL3-targeted therapeutic is insufficient to demonstrate possession of the genus as a whole. The breadth of the claims encompasses DLL3-targeted therapies which the present inventors were not in the possession of, or which were not known to the inventors. The instant disclosure does not allow one of skill in the art to visualize or recognize the structure of additional DLL3-targeted therapies that could be used to practice the claimed method. Therefore, the claims fail to meet the written description requirement because the claims encompass a significantly large genus of DLL3-targeted therapies which are not adequately described in the specification.
Response To Arguments
6. In the response the Applicants traversed the rejection under 35 USC 112(a)-Written Description. The Applicants argue that the specification describes at least four distinct categories of DLL3-targeted therapeutics: (1) anti-DLL3 antibodies such as rovalpituzumab; (2) antibody-drug conjugates such as rovalpituzumab tesirine; (3) DLL3-targeted CAR-T cells; and (4) DLL3-targeted CAR-NK cells. These are structurally distinct modalities representing different classes of therapeutic agents, including biologics, conjugate drugs, and engineered cellular therapies. The disclosure of multiple representatives from structurally diverse categories satisfies the written description requirement for the recited genus.
This argument has been fully considered but is not persuasive. The claims require administering a DLL3-targeted therapy. As broadly recited, the DLL3-targeted therapy may be any organic or inorganic compound, including any small molecule, antibody, antisense RNA, siRNA, shRNA, miRNA, ribozyme, gene therapy, aptamer or enzyme. As the District Court in University of Rochester v. G.D. Searle & Co., Inc. (2003 WL 759719 W.D.N.Y.) stated “In effect, then, the '850 patent claims a method that cannot be practiced until one discovers a compound that was not in the possession of, or known to, the inventors themselves. Putting the claimed method into practice awaited someone actually discovering a necessary component of the invention.” This is similar to the current situation since the breadth of the current claims encompasses the use of therapeutic agents which the present inventors were not in the possession of, or which were not known to the inventors. The rejection is maintained.
Claim Rejections - 35 USC § 103
7. 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 should not be negated by the manner in which the invention was made.
8. Claims 1, 54, 56, 483, and 484 are rejected under 35 U.S.C. 103 as being unpatentable over Owen (Journal of Hematology & Oncology 2019 12:61) in view of GSE66298 ( GEO Accession GSE66298 Pub 7/14/2015 found online at https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE66298).
Owen teaches that DLL3 is being explored as a potential therapeutic target in SCLC. Owen discloses three DLL3-specific therapies being developed for the treatment of SCLC: the antibody-drug conjugate rovalpituzumab tesirine, the bispecific T cell engager immuno-oncology therapy AMG 757, and the chimeric antigen receptor T cell therapy AMG 119 (abstract). Owen describes ongoing clinical trials with these DLL3-targeted agents in SCLC (Table 1). Owen teaches that rovalpituzumab is DLL3-specific IgG1 monoclonal antibody that is administered along with chemotherapy (see, Table 1, page 2, col 2). Owen teaches that rovalpituzumab is being tested in the first line, second line, and maintenance settings (Table 1).
Owen does not teach administering a DLL3- targeted therapy to a subject having tumor DNA with differential methylation at cg20728514.
However, GSE66298 discloses the methylation level of cg20728514 in 11 SCLC patient tumors. As shown in the screen shot below, subject GSM1619033 has a tumor with differential methylation of cg20828514 in comparison to the other SCLC subjects.
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Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have administered a DLL3- targeted therapy to the SCLC patients of GSE66298. In the instant case Owen discloses ongoing clinical trials testing DLL3- targeted therapy for the treatment of SCLC. Based on the teachings of Owen it would have been obvious to administer DLL3-targeted therapy to ANY subject with SCLC, including those which have differential methylation at cg20728514, for the benefit of further studying DLL3 as a potential therapeutic target in SCLC.
Claim 484 recites “wherein the subject is classified as having SCLC-A based on differential methylation at cg20728514”. However, claim scope is not limited by claim language (such as wherein clauses) that suggests or makes optional but does not require steps to be performed. In the instant case there are no active process steps of classifying the subject.
7. Claim 44 is rejected under 35 U.S.C. 103 as being unpatentable over Owen (Journal of Hematology & Oncology 2019 12:61) in view of GSE66298 ( GEO Accession GSE66298 Pub 7/14/2015 found online at https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE66298) as applied to claim 1 above and in further view of Lissa (Transl Lung Cancer Research 2016 5(5):492-504).
The teachings of Owen and GSE66298 are discussed above.
The combined references do not teach a method wherein the tumor DNA is ctDNA.
However Lissa teaches that molecular alterations found in the DNA of tumor cells, such as mutations, translocations and methylation, are reflected in DNA that is released from the tumor into the bloodstream. Thus, in recent years, circulating tumor DNA (ctDNA) has gained increasing attention as a noninvasive alternative to tissue biopsies and potential surrogate for the entire tumor genome (abstract).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Owen and GSE66298 by administering a DLL3 targeted therapy to a subject having ctDNA with differential methylation at cg20728514. Based on the teachings of Lissa one of skill in the art would have been motivated to look at ctDNA since methylation differences in tumors are reflected in ctDNA and ctDNA can be obtained using less invasive methods.
Response To Arguments
8. In the response the Applicants traversed the rejection under 35 USC 103. The Applicants argue that even though GSE66298 shows methylation levels at cg20728514 in some SCLC patients, GSE66298 provides no teaching, suggestion, or motivation to use cg20728514 methylation status as a biomarker to select patients for DLL3-targeted therapy. GSE66298 is simply a database deposit of methylation array data; it does not correlate methylation status with treatment response, subtype classification, or therapeutic selection. Further they argue that Owen teaches that DLL3-targeted therapies are being developed for SCLC broadly, without any reference to methylation-based patient selection. There is no teaching in the cited art that differential methylation at cg20728514 identifies a particular SCLC patient population that would benefit from DLL3- targeted therapy over other treatment modalities. They argue that the present application discloses for the first time that cg20728514 is associated with the SCLC- A subtype, which is characterized by ASCL1 expression and vulnerability to BCL2 inhibitors and DLL3-targeted therapies
These arguments have been fully considered but are not persuasive. The claims do not recite any correlations between cg20728514 and SCLC. Therefore the prior art is not required to teach this. Further the claims do not recite any active process steps of selecting a patient for DLL3-target therapy based on differential methylation at cg20728514. In view of the prior arts cited it would have been obvious to administer DLL3-targeted therapy to ANY subject with SCLC, including those which have differential methylation at cg20728514, for the benefit of further studying DLL3 as a potential therapeutic target in SCLC. The rejection is maintained.
Regarding Claim 44 the Applicants argue that the prior art of Lissa does not cure the deficiencies of Owen and GSE66298.
This argument has been fully considered but is not persuasive. The Applicants arguments regarding what is missing in the combination of Owen and GSE66298 have been fully addressed above. The response to Applicants arguments, as set forth above, applies equally to this ground of rejection.
Improper Markush Grouping Rejection
10. Claims 1, 44, 54, 56, and 483-484 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The claims recite the following Markush group: one or more methylation sites selected from the methylation sites of Table 2, Table 7, Table 15, Table 20, and Table 27.
The Markush grouping is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
MPEP 2117(II) states that “A Markush claim may be rejected under judicially approved “improper Markush grouping” principles when the claim contains an improper grouping of alternatively useable members. A Markush claim contains an “improper Markush grouping” if either: (1) the members of the Markush group do not share a “single structural similarity” or (2) the members do not share a common use. Supplementary Guidelines at 7166 (citing In re Harnisch, 631 F.2d 716, 721-22, 206 USPQ 300, 305 (CCPA 1980)).
MPEP 2117(II) further state that alternatives (1) share a “single structural similarity” when they belong to the same recognized physical or chemical class or to the same art-recognized class and (2) share a common function or use when they are disclosed in the specification or known in the art to be functionally equivalent in the context of the claimed invention.
MPEP § 2117(II)(A) states that “A recognized physical class, a recognized chemical class, or an art-recognized class is a class wherein “there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention. In other words, each member could be substituted one for the other, with the expectation that the same intended result would be achieved”. Herein the members of the Markush grouping are all methylation sites. These do not belong to the same recognized physical or chemical class or to the same art-recognized class because there is no expectation from the art that each of the recited methylation sites would function in the same way in the claimed method. It is only in the context of this specification that it was disclosed that all members of this group may behave in the same way in the context of the claimed invention.
MPEP § 2117(II)(B) states that “Where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as explained in subsection IIA above, the members of the Markush grouping may still be considered to be proper where the alternatives share a substantial structure feature that is essential to a common use. Again the members of the Markush grouping are all methylation sites. While they are all made up of a nucleotide that is potentially methylated and flanked by additional nucleotides, this structure is not essential to any asserted common use.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Response To Arguments
11. In the response the Applicants traversed the improper Markush rejection. The Applicants argue that the methylation sites recited in Tables 2, 7, 15, 20, and 27 all share a common structural feature: they are CpG dinucleotide sites susceptible to cytosine methylation. Each methylation site identifier (e.g., cg20728514) corresponds to a specific CpG dinucleotide at defined genomic coordinates. Moreover, these methylation sites share a common use: they are all biomarkers for the SCLC-A subtype and guide selection of the same therapeutic modalities, namely, BCL2 inhibitors or DLL3-targeted therapies.
This argument has been fully considered but is not persuasive. Each methylation site/cg number contains a CpG dinucleotide flanked by sequences on each side. The flanking sequences do not share any common structure. While they are made up of the same four bases, they do not share any significant similarity in the order in which those bases are arranged. Thus the structures of the methylation sites/cg numbers are different and they do not share a “single structural similarity”. The rejection is maintained.
12. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMANDA HANEY whose telephone number is (571)272-8668. The examiner can normally be reached Monday-Friday, 8:15am-4:45pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu-Cheng Shen can be reached at 571-272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/AMANDA HANEY/Primary Examiner, Art Unit 1682
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