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 .
The claims filed 5/18/2026 are under consideration.
The amendments and arguments presented in the papers filed 5/18/2026 ("Remarks”) have been thoroughly considered. The issues raised in the Office action dated 2/19/2026 listed below have been reconsidered as indicated.
a) The objection of claim 1 is withdrawn in view of the amendments to the claims.
b) The rejections of claims 134, 135 and 136 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, are withdrawn in view of the Remarks (p. 29-32).
The Examiner’s responses to the Remarks regarding issues not listed above are detailed below in this Office action.
New and modified grounds of rejection necessitated by amendment are detailed below and this action is made FINAL.
Election/Restrictions
Applicant elected with traverse of Group I, claims 1, 24, 26, 31, 33, 35, 37, 43, 47, 54, 67, 71, 73, 77, 83, 87-90, 107, 134-137, 139, 140, 143, 146-148, 152, 160, 165, 168, 173, 176, 177, 179, and 181-182, in the reply filed on 11/24/2025.
New claims 184 and 185 are included with Group I.
Claims 1(II)-1(IV), 109, 110, 156, 160 and 165 were withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 11/24/2025.
It is noted that parts (II)-(IV) of claim 1 have been cancelled. New claim 184 and 185 do not correspond to any of the cancelled parts of claim 1.
The following election of species requirements have been reconsidered and are withdrawn: A, B, C, D, F, H, I, K, L and M.
Applicant elected the following species:
E. An immune checkpoint inhibitor of claim 110 – anti-PD-1 antibody
G. An tubulin disrupting agent of claim 18, 143, 146, and 147 - MMAE
J. A first dose and a second dose of claim 160 and 165 - a first dose of the ADC is a dose of about 1.25 mg/kg of the subject's and a second dose of about 0.25 mg/kg.
Priority
The present application is a 371 national stage entry of PCT/US21/37994 (filed 6/18/2021), which claim benefit of US provisional application 63/041,636 (filed 6/19/2020).
Priority is recognized.
Information Disclosure Statement
The listing of references in the specification or the citation of references throughout the body of the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892 or cited on a submitted IDS, they have not been considered.
Specification
The disclosure is objected to because of the following informalities: in para. 326 the specification fails to provide a complete paragraph.
Appropriate correction is required. Applicant is cautioned regarding the incorporation of new matter into the specification.
Claim Objections
Applicant is advised that should claim 1 be found allowable, claims 184 and 185 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m). The claims differ in the preamble. However, the active method steps are the same between the three claims as the body of the claims are identical to one another. There is nothing of record that demonstrates how the preambles of claims 184 and 185 alter the scope of the claims relative to claim 1.
Claim Rejections - 35 USC § 112
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, 24, 26, 31, 33, 35, 37, 43, 47, 54, 67, 71, 73, 77, 83, 87, 88, 89, 90, 107, 134, 135, 137, 139, 140, 143, 146, 147, 148, 152, 168, 173, 176, 177, 179, 181, 182, 184 and 185 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 following rejection has been modified to clarify the issues being raised by the Examiner.
Scope of ADC Set I and Set II Marker Genes
Claim 1 is drawn to methods. The claim requires a step of “determining an increase of expression of one or more ADC Set I Marker genes”. The term “ADC Set I Marker genes” is detailed in claim 1 as comprising “one or more major histocompatibility complex (MHC) signature genes, one or more toll-like receptor (TLR) family genes, one or more interleukin receptor family genes, one or more immune checkpoint receptor genes, one or more receptor tyrosine kinase genes, one or more IFN receptor family genes, one or more TNF family receptor genes, one or more inhibitory immunoreceptor genes, and/or one or more metabolic enzyme genes”. The instant specification provides a similar definition in para. 314:
the term "ADC Set I Marker genes" refers to any set or subset of the follow group of genes: MHC signature genes, TLR family genes, interleukin receptor family genes, immune checkpoint receptor genes, receptor tyrosin kinase genes, IFN receptor family genes, TNF family receptor genes, inhibitory immunoreceptor genes, and/or metabolic enzyme genes, each as defined herein, in any combination or permutation.
Dependent claim 87 requires a step of “determining an increase of expression of one or more ADC Set II Marker genes in the subject”. The term “ADC Set II Marker genes” is detailed in claim 87 as comprising “one or more genes selected from the group consisting of ER stress genes, ER/mitochondria ATPase genes, cell death genes, T cell stimulator genes, macrophage/innate immunity stimulator genes, chemoattractant genes, Rho GTPase genes, Rho GTPase regulator genes, mitotic arrest genes, siglec family genes, GO positive autophagy regulator genes, and GTPase related kinase genes”. The instant specification provides a definition in para. 327:
the term "ADC Set II Marker genes" is intended to mean genes that have both attributes of: (1) which are not ADC Set I Marker genes and (2) whose expression correlates with the increase in immunogenic cell death (ICD).
The full scope of ADC Set I and ADC Set II marker genes is not adequately exposed. While applicant is allowed to be their own lexicographer, the new terms need to be adequately described. The ADC Set I and ADC Set II marker do not correspond to any known gene sets or classifications (e.g., GO terms, KEGG terms, etc.). The sets are defined in broad and generic terms such that one is not adequately able to determine which genes and which genes are not involved with having increased expression determined.
The instant specification states that in a nude mouse, xenograft model using bladder cancer cell lines engineered to express Nectin-4, 1267 genes were identified as being differentially regulated genes, i.e., went up or down between the untreated samples versus samples treated with enfortumab vedotin, in tumor samples or cell line samples (para. 220, 915, 921). The instant specification does not identify the 1267 genes by name, or which genes had expression that went up versus down. For this reason alone, the application fails the written description requirement because genes encompassed claim and required to have an increase in expression are not sufficiently disclosed.
Those genes that have expression that “went up” are relevant to the claimed methods in particular, as “determining an increase of expression of one or more ADC Set I Marker genes in the subject” is required. The instant specification does identify a subset of genes in the Figures that have differential expression between treated and untreated mice or those given a non-binding ADC (Figs. 6, 7, 8, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 and 21) but figures further include those that are not differentially expressed, e.g., eotaxin/CCL11 (Fig., 10C), Rfxap (mouse), Tlr7 (mouse) (Fig. 13), Tlr3 (mouse) (Fig. 13), PVRIG (human) (Fig. 15B), and those with no mention of whether they are significant, e.g., RFXAP (human), RFXANK (human) (Fig. 11A), CD40 (human) (Fig. 16C) and XBP-1L (Fig. 18). The specific genes (both significant and not significant genes) include:
Fig. 6: F4/80 positive cells; and CD11c positive cells.
Fig. 7: HLA-A (human); HLA-B (human); HLA-C (human); HLA-E (human); HLA-F (human); TAP2 (human); IRF7 (human); NFKB2 (human); RELA (human); and STAT2 (human).
Fig. 8: HLA-DMA (human); HLA-DMB (human); HLA-DRB1 (human); HLA-DRA (human); HLA-DPA1 (human); HLA-DPB1 (human); H2-T24 (mouse); H2-Aa (mouse); H2-Ab1 (mouse); H2-Eb1 (mouse); Tap1 (mouse); Lst1 (mouse); Ltb (mouse); Aif1 (mouse); Tnf (mouse); MHC-II; IL-1A; TGF-alpha; IP-10/CXCL10; IFN-gamma; and MIP1beta.
Fig. 10: MIG/CXCL9; IP10/CXCL10; IL-1alpha; M-CSF/CSF1; Eotaxin/CCL11; MIP1alpha; MIP1beta; and MCP1.
Fig. 11: CTCF (human); CIITA (human); RFX1 (human); RFX5 (human); RFX7 (human); RFXAP (human); and RFXANK (human).
Fig. 12: Rfx1 (mouse); Rfxap (mouse); Rfxank (mouse); Ciita (mouse); Rfx5 (mouse); Spi1 (mouse); Nfya (mouse); Nfyc (mouse); and Irf8 (mouse).
Fig. 13: Tlr9 (mouse); Tlr8 (mouse); Tlr7 (mouse); Tlr3 (mouse); and Siglec1 (mouse).
Fig. 14: Il2ra (mouse); Il2rb (mouse); Il2rg (mouse); Il21r (mouse); Il27r (mouse); Il1rn (mouse); Il17ra (mouse); Il3ra (mouse); IL1R1 (human); IL17RA (human); IL17RC (human); IL20RA (human); and IL22RA1 (human).
Fig. 15: VTCN1; CD276 (human); PVRIG (human); PVRL2 (human); Tigit (mouse); and LAG3 (human).
Fig. 16: Csf1r (mouse); Pdgfrb (mouse); Tek/Tie2 (mouse); Flt3 (mouse); Ifnar1 (mouse); Ifnar2 (mouse); CD40 (human); TNFRSF1A (human); TNFRSF21 (human); Tnfrsf1b (mouse); Tnfrsf1a (mouse); and Tnfrsf21 (mouse).
Fig. 17: Havcr2 (mouse); Vsir (mouse); IDO1 (human); Tdo2 (mouse); Elf2ak2 (mouse); Acss1 (mouse); Acss2 (mouse); ACSS1 (human); and ACSS2 (human).
Fig. 18: BCL2L11 (human); BCAP31 (human); SERINC3 (human); DAP2IP (human); ERN1 (human); ATF6 (human); XBP-1S; XBP-1L; ERP29 (human); NCK2 (human); PPP1R15A (human); UBQLN2 (human); EDEM2 (human); BAG6 (human); BOK (human); TRAF2 (human); and c-JUN (human).
Fig. 19: CDC42 (human); RhoA (human); RhoB (human); RhoC (human); RhoF (human); RhoG (human); DAP2IP (human); ARHGEF18 (human); ARHGEF5 (human); RASAL1 (human); ROCK1 (human); and PAK4 (human).
Fig. 20: BCL2L11 (human); ROCK1 (human); TSC1 (human); TSC2 (human); BNIP3 (human); BNIP3L (human); BAG3 (human); MFN2 (human); RIPK1 (human); RIPK4 (human); HDAC6 (human); STK11 (human); ULK1 (human); FOXO1 (human); FOXO3 (human); and MUL1 (human).
Fig. 21: ATP2A3 (human); MT-ATP6 (human); MT-ATP8 (human); FAS (human); Bax (human); BCL2L1 (human); BOK (human); CDKN1A (human); GADD45B (human); E4F1 (human); DDIAS (human); CDC14B (human); CDK1 (human); DAPK1 (human); and CCND1 (human).
Fig. 22A and 22B provides plots of human genes, human signature genes and mouse signature genes, but none of the gene names are listed in clear manner.
Fig. 22C provides “GO Terms”, but are not commensurate in scope with the genus of genes recited in claim 1 and 87.
There is no indication whether the 1267 differentially expressed genes were between untreated and AGS-22C3E, untreated and non-binding ADC or AGS-22C3E and non-binding ADC.
The specification also describes individual genes in paragraphs 357 to 501 describes numerous genes. However, whether those genes are encompassed by ADC Set I marker genes, ADC Set II marker genes or by both ADC Set I and II marker genes is not disclosed.
Scope of “subject” in which ADC Set I and Set II Marker Genes increases are determined
The genes are a mixture of mouse (host) genes and human (transplanted tumor) genes. The genes were identified by RNA-seq, which screens the entire transcriptome from the model. Thus, applicant is not in possession in the context of claim 1 and 87 of any genes outside of the 1267 genes because they were not differentially expressed, and thus were not of interest to applicant within the context of the claimed methods. For example, the RNA-seq data would provide information regarding TLR4 (which is broadly encompassed by “one or more toll-like receptor (TLR) family genes”), but applicant does not disclose it as a gene that was differentially regulated. There is no validation of the observed genes in fully immunocompetent mice (nude mice lack T cells) or in human patients. There is no description of whether the claimed “genes” are relevant in purely mouse systems, purely human systems or if they are only relevant in mouse-human hybrid systems.
Scope of a “sample” in which ADC Set I and Set II Marker Genes are determined
There is no guidance as two whether patient samples other than a tumor sample, such as blood samples, normal tissue samples, etc., would be informative regarding the differential expression of any of the 1267 genes identified by applicant but that are not fully disclosed.
The instant specification is an invitation for one to carry out an analysis to identify ADC Set I and II Marker genes, with no reasonable expectation of success that the same set of 1267 genes would be identified.
The limited number of genes specifically identified, do not reasonably provide support for the entire scope of the claimed ADC Set I and II Marker genes. The generic gene subsets described in the specification cover far more than 1267 genes, and there is no clear guidance regarding which 1267 genes applicant specifically identified and those applicant was not interested in or those that were not informative in the context of claims 1 and 87, i.e., no differential expression. Furthermore, within the identified subsets of genes encompassed by the ADC Set I and II Marker genes, e.g. MHC signature genes, TLR family genes, interleukin receptor family genes, etc., are quite broad. There is no guidance which “MHC signature genes” applicant identified as within the 1267 genes and which were not.
By way of example, the term “MHC signature genes” is not an art recognized term or classification of genes. None of the “GO Terms” provided in Fig. 22C specifically relates to “MHC signature genes”. For example, none of the “GO Terms” relate to the immune response or antigen presentation. The instant specification provides a very broad and generic description of what “MHC signature genes” may encompass (para. 315-326).
By way of another example, no description of the scope of “GTPase related kinase genes” is provided in para. 326.
“MHC signature genes” broadly encompasses “STAT family genes”, which include STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6. The instant specification only provides expression data for STAT2. There is no indication that the RNA-seq data also observed differential expression of STAT1, STAT3, STAT4, STAT5a, STAT5b and STAT6. The STAT family members have diverse functions. STAT2 relates to antiviral genes in response to type I interferons, whereas STAT3 relates to cell growth, differentiation and inflammation, STAT4 is expressed in the testes and myeloid cells, STAT5 relates to hematopoietic cell development and lactation and STAT6 relates to allergic reactions and T-helper 2 cells. STAT6 relates to activation by IL-4 and IL-13. There is no indication that IL-4 or IL-13 expression was observed to have increased expression. There is no reasonable explanation of how the entire STAT family genes are implicated solely based on the disclosure of only STAT2 as being differentially expressed.
In conclusion, the limited number of differentially expressed gene species does not support the full scope of the genus of ADC Set I and Set II Marker Genes encompassed by the claims 1 and 87. The full scope of what the ADC Set I and Set II Marker Genes encompasses is not clearly disclosed such that the one of ordinary skill can readily determine which genes applicant had contemplated and/or demonstrated possession of in the context of the methods of claims 1 and 87. The specification lists numerous pathways that implicates genes far beyond the 1267 genes applicant actually identified as being differentially regulated. There is no guidance based on the 1267 genes, which are not fully disclosed, that one may use to identify additional genes that may be relevant within the claimed methods. Lastly, because the instant specification relied upon RNA-seq data, information about the entire transcriptome was collected. One would not have found applicant to be in possession of genes outside of the 1267 genes applicant found to be differentially expressed. The ordinary artisan would have concluded that other genes within the transcriptome were not of interest to the claimed methods based on the analysis of the instant specification, and therefore, applicant did not have possession of any additional genes relevant to the claimed methods.
The instant specification describes using the 1267 differentially expressed genes to identify “signatures” that went up or down. However, there is no indication of which genes that are to have their expression determined according to the claimed methods belong to these signatures. Further, there is no indication that measuring any of the genes within these “signatures” are relevant by themselves to determining how to proceed with the ADC treatment of the subject according to the claimed methods.
Claims 24, 26, 31, 33, 35, 37, 43, 47, 54, 67, 71, 73, 77, 83, 87, 88, 89, 90, 107, 134, 135, 137, 139, 140, 143, 146, 147, 148, 152, 168, 173, 176, 177, 179, 181 and 182 depend from claim 1 and are rejected for the same reason provided above.
Response to the traversal of the Written Description rejections
The Remarks summarize the rejection for lack of written description (p. 24).
The Examiner’s position is detailed above.
The Remarks argue claim 87 has been amended to recite the genus of genes encompassed by ADC Set II Marker genes and amended claim 87 now identifies the ADC Set II Marker genes (p. 24-25).
The argument has been fully considered but is not persuasive. Claim 87 remains rejected for the reasons provided above. The full scope individual genes encompassed ADC Set II marker genes is not adequately described. The limited number of species disclosed in the specification does not adequate support the entire genus of claim 87 or to readily identify what the 1267 genes the instant specification generically identifies as being differentially expressed.
The Remarks argue the instant specification provides a detailed disclosure of the gene expression result from the RNA-seq analysis, which fully supports the claimed ADC Set I and ADC Set II Marker genes (p. 25). The Remarks argue the Examples describes assays and argues Example 3 applies the Example 1 assays to identify the marker genes within each of ADC Set I and Set II (p. 25). The Remarks summarize what was done in Examples 2 and 3 (p. 25-26). The Remarks point to particular genes where expression data was provided (p. 26-27). The Remarks argue a person of ordinary skill in the art can readily identify the same set of genes following the protocol disclosed in the instant specification and a person of ordinary skill in the art can readily determine from each figure which genes went up and which went down. See p. 26-27).
The arguments have been fully considered but are not persuasive. The limited number of species in the form of particular genes does not adequately provide scope for the entire scope of the claimed genus of genes for which their expression is to be observed. Additionally, any disclosed genes that are a decrease in expression after ADC treatment is not relevant as the claim requires determining an increase of expression. The various sets of genes described as being encompassed by the ADC Set I and Set II marker genes are not defined or limited in a meaningful manner. The sets are quite diverse in scope and because some of the genes were observed to be differentially expression does not support the conclusion that all the genes within that set were also differentially expressed. It is the examiner’s position that the RNA-seq and analysis should have identified all the genes differentially expressed. Even if the 1267 genes represent the entire scope of DC Set I and Set II marker genes of interest to applicant, their identities are not disclosed.
Regarding the notion that the ordinary artisan could repeat these experiments and identify the relevant genes, that is not the standard under the written description requirement. The instant specification does not readily identify which genes applicant had possession of. While common knowledge in the field does not need to be disclosed, the set of genes encompassed by ADC Set I and Set II marker genes is not common knowledge. The terms used in the claims are loosely defined in the specification and are not art recognized classifications. It is undue experimentation to require the ordinary artisan to repeat the experiments of the present application in order to determine the full scope of genes applicant had possession of at the time of filing. Furthermore, there is no indication that in repeating the experiments one would reasonably identify only 1267 differentially expressed genes or that those genes would be exactly the same as those identified by applicant.
Claim Rejections - 35 USC § 112
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, 24, 26, 31, 33, 35, 37, 43, 47, 54, 67, 71, 73, 77, 83, 87, 88, 89, 90, 107, 134, 135, 136, 137, 139, 140, 143, 146, 147, 148, 152, 168, 173, 176, 177, 179, 181, 182 and 184-185 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.
The following are new rejections necessitated by the amendments.
Regarding claims 1, 184 and 185, it is unclear if step (2) is a result of the “comparing” of step (3) or if steps (2) and (3) are separate and unrelated steps.
The following is a maintained rejection that has been modified to clarify the Examiner’s position.
Regarding claims 1, 184 and 185, the claim requires a step of “determining an increase of expression of one or more ADC Set I Marker genes in the subject” in step (2). Step (3) broadly encompasses “comparing” and alternative steps based on whether or not “increased” expression was observed. It is unclear whether the methods encompass embodiments in which alternatives based on observing no increase expression are encompassed by the claim because the claim requires “determining an increase of expression of one or more ADC Set I Marker genes in the subject”. It is unclear how one “determines an increase” and have the claim encompass discontinuing administration to the subject the ADC when the expression of the one or more ADC Set I Marker genes is not increased after ADC administration.
Claims 24, 26, 31, 33, 35, 37, 43, 47, 54, 67, 71, 73, 77, 83, 87, 88, 89, 90, 107, 134, 135, 136, 137, 139, 140, 143, 146, 147, 148, 152, 168, 173, 176, 177, 179, 181 and 182.
Response to the traversal of the 112(b) rejections
The Remarks argue the amendments address the 112(b) rejections (p. 27-29).
The arguments have been fully considered but are not persuasive because the arguments do not address the above issues.
Claim Rejections – Improper Markush
Claims 1, 26, 33, 35, 47, 54, 71, 83, 87 and 90 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.
Claims 1, 26, 33, 35, 47, 54, 71, 83, 87 and 90 include Markush groups listing genes as the alternatives. The different genes encompassed by the claims have different structures (both in terms of nucleic acid sequences and amino acid sequences) and have different functions or uses. Also, absent the specification, the sets of genes are not art-recognized as being in a class of genes relevant to treatment with the ADC described in claim 1.
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 the traversal of the Improper Markush Group rejections
The Remarks summarize the improper Markush group rejection (p. 32).
The Examiner’s position is detailed above.
The Remarks argue Applicants submit that the genes recited in claims 1, 26, 33, 35, 47, 54, 71, 83, and 90 are grouped by their art-recognized functional classification, e.g., MHC signature genes, TLR family genes, interleukin receptor family genes, immune checkpoint receptor genes, etc. See p. 33.
The arguments have been fully considered but are not persuasive. The issue is that between subsets of the Markush group there is no art recognized functional relationship. The Remarks do not address the common structure and function between subsets, such as between MHC signature genes and TLR family genes, or TLR family genes and interleukin receptor family genes.
The Remarks argue the groups are not arbitrary groupings; they are families defined by well-established structural and functional characteristics recognized in the art (p. 33).
The arguments have been fully considered but are not persuasive. The arguments do not identify any common structure or function and where in the art they are recognized. The Remarks merely assert they have structural and functional characteristics recognized in the art.
The Remarks argue each group shares a common use in the context of the claimed invention and they are markers whose expression changes in response to EV treatment, and their expression changes are used to guide treatment decisions. As described above, the specification demonstrates that genes within these families are identified as being differentially expressed in response to EV treatment. See p. 33.
The arguments have been fully considered but are not persuasive. While the instant specification demonstrates they specific genes may have a common use, there is no indication regarding the common structure responsible for the common use or the art recognized class. A search of the subset names of claims 1 and 87 did not provide a well-defined group of genes. Second, the genus of genes as a whole is not part of a single art recognized class. The genus is a collection of distinct subset of genes. Third, there is no evidence that the different species are functionally equivalent. For example, even within a subset such as TLR family genes, the species are not functionally equivalent or have a common use. TLR4 is used to detect endotoxin and TLR9 is used to detect unmethylated CpG DNA motifs.
Claim Rejections - 35 USC § 103
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 (i.e., changing from AIA to pre-AIA ) 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.
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.
The factual inquiries 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 24, 26, 31, 33, 35, 37, 43, 47, 54, 67, 71, 73, 77, 83, 87-90, 107, 134-137, 139, 140, 143, 146-148, 176, 177, 184 and 185 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bekos (Cancers. 2019. 11:698 and Supplementary Materials; published 5/20/2019).
Regarding claims 1, 24, 26, 31, 33, 35, 37, 43, 47, 54, 67, 71, 73, 77, 83, 87-90, 176 and 177, Bekos teaches determining expression of the following genes using RNA-sequencing in ovarian tumor tissues: LST1, IFNAR1, HLA-A, IL2RA, VSIR, TLR8, TLR7, CSF1R, EDEM2, IDO1, ERP29, CD276, CIITA, REL, TNFRSF1A, IFNAR2 and IL20RA (Table S5; a truncated copy is provided listing relevant genes).
The genes were down-regulated in Nectin-4 high expressing tumors (Table S5), meaning if the Nectin-4 high cells are eliminated, their expression in the tumor should increase.
Bekos further teaches that enfortumab vedotin was known as a treatment for Nectin 4 expressing cancers (p. 17-18 of 27). Enfortumab vedotin is broadly encompassed by the required ADC as it is the same drug the instant specification relied upon.
It would have been prima facie obvious to have treated the patients of Bekos with enfortumab vedotin to treat their nectin-4 high expression tumors. One would have been motivated to look at gene expression after treatment to evaluate the effectiveness of the treatment. One would reasonably infer that removing a Nectin 4-expressing cell from a tumor would make it look more like a Nectin-4 negative tumor, which has relative increases in the expression of the genes as compared to Nectin 4-expressing tumors. Furthermore, if the gene expression indicates that Nectin 4-expressing tumor cells are being reduced after treatment, it would have been prima facie obvious to continue giving enfortumab vedotin. However, if the gene expression indicates that Nectin 4-expressing tumor cells are not being reduced after treatment, it would have been prima facie obvious to stop giving the same dose of enfortumab vedotin to the patient as it is not being effective.
Regarding claim 107, one would reasonably expect that the removal of Nectin 4-expressing cells would result in tumors having gene expression that is similar to Nectin 4-negative tumors, achieving a fold increase that is encompassed by the claimed ranges.
Regarding claims 134-137, 139, 140, 143 and 146-148, as noted above Bekos teaches and suggests using enfortumab vedotin as a treatment. In view of the instant specification, enfortumab vedotin has all the elements detailed in claims 134-137, 139, 140, 143, 146, 147 and 148.
Claim(s) 152 and 168 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bekos (Cancers. 2019. 11:698 and Supplementary Materials; published 5/20/2019) in view of Satpayev (US 8,637,642 B2).
Regarding claims 152 and 168, Bekos renders obvious the elements of claim 1 as described above and as required by claims 152 and 168.
Bekos does not teach the additional elements specific to claims 152 and 168.
However, Satpayev teaches aspects known about ADCs targeting 191P4D12/Nectin-4.
Regarding claim 152, Satpayev teaches that the ADC is given at a dose of 5 or 10 mg/kg (col. 70, lines 44-67).
Regarding claim 168, Satpayev teaches the ADC is administered via intravenous injection (col. 70, lines 44-67).
It would have been prima facie obvious to have delivered the enfortumab vedotin taught by Bekos based on the parameters of Satpayev demonstrating how such drugs are delivered.
Claim(s) 173 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bekos (Cancers. 2019. 11:698 and Supplementary Materials; published 5/20/2019) in view of Adler (US 2015/0353640 A1).
Regarding claim 173, Bekos renders obvious the elements of claim 1 as described above and as required by claim 173.
Bekos does not teach the additional elements specific to claim 173.
However, Adler teaches formulating a pharmaceutical composition comprising an antibody by including excipients of L-histidine, polysorbate 20, and trehalose (para. 87).
It would have been prima facie obvious to one of ordinary skill at the time of filing to use the excipients as taught by Adler to formulate the enfortumab vedotin composition noted by Bekos. One of ordinary skill in the art would have been motivated to do so, because Bekos teaches a pharmaceutical composition comprising an antibody drug conjugate (ADC), and Adler further teaches formulating a pharmaceutical composition comprising an antibody by including excipients of L-histidine, polysorbate 20, and trehalose. Therefore, the combined teachings provide a reasonable expectation of success in formulating the pharmaceutical composition.
Claim(s) 179 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bekos (Cancers. 2019. 11:698 and Supplementary Materials; published 5/20/2019) in view of Lopez (WO 2017/042210 A1).
Regarding claim 179, Bekos renders obvious the elements of claims 1 and 176 as described above and as required by claim 179.
Bekos does not teach the additional elements specific to claim 179.
However, Lopez teaches that Nectin 4 is mainly expressed in triple-negative breast tumors (p. 1).
It would have been prima facie obvious to the ordinary artisan to have modified the method of Bekos by using, treating and analyzing triple-negative breast tumors. One would have been motivated to do so because enfortumab vedotin targets Nectin 4 and it would have been obvious to try and target those tumors specifically.
Claim(s) 181 and 182 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bekos (Cancers. 2019. 11:698 and Supplementary Materials; published 5/20/2019) in view of Mar (Journal of Oncology Practice. 2019. 15(8):421-428).
Regarding claims 181 and 182, Bekos renders obvious the elements of claims 1 and 176 as described above and as required by claims 181 and 182.
Bekos does not teach the additional elements specific to claims 181 and 182.
However, Mar teaches that Nectin 4 is overexpressed in 97% of all urothelial carcinomas (p. 425), which includes both papillary urothelial carcinoma and flat urothelial carcinoma subtypes. Urothelial carcinoma is a form of non-muscle invasive bladder cancer.
It would have been prima facie obvious to the ordinary artisan to have modified the method of Bekos by using, treating and analyzing various types of urothelial and bladder tumors. One would have been motivated to do so because enfortumab vedotin targets Nectin 4 and it would have been obvious to try and target those tumors specifically.
Response to the traversal of the 103 rejections
The Remarks summarize the rejections over Bekos (p. 33-34).
The Examiner’s position is detailed in the above rejections.
The Remarks argue Bekos does not disclose or suggest the administration of any ADC to a patient, does not determine changes in gene expression in response to ADC treatment, and does not use gene expression changes to guide treatment decisions (p. 34).
It is the Examiner’s position that the teachings of Bekos renders those elements obvious when considered in its entirety. Bekos does teach the ADC EV was known and used to treat nectin-4 expressing cancer cells.
The Remarks argue the specific correlation between the claimed anti-nectin-4 ADC, defined by the particular CDRs of SEQ ID NOs: 22 and 23 conjugated to MMAE, and the upregulation of genes within the art-recognized families recited in the claims was not foreseeable from Bekos's observational data about pre-existing expression differences in ovarian cancers (p. 24).
Bekos teaches genes that are expressed in nectin-4 positive cancer cells. It is known that EV targets and eliminates nectin-4 positive cancer cells as demonstrated by Bekos. Thus, one would be able to evaluate the response to the EV treatment by monitoring the change in expression that would occur if the nectin-4 positive cells are actively being removed from the tissue. The ordinary artisan would recognize that the gene expression of Bekos represent biomarkers which can be tracked over time and in response to treatment with EV.
The Remarks argue Bekos provides no motivation to administer an ADC, no motivation to monitor post-treatment gene expression, and no reasonable expectation that the specific families identified in the instant specification would respond to the specific ADC recited.
It is noted that the Supreme Court ruling for KSR Int’l Co. v. Teleflex, Inc (No 04-1350 (US 30 April 2007) forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See Ex parte Smith (USPQ2d, slip op. at 20 (Bd. Pat. App. & Interf. June 25, 2007). The ordinary artisan would recognize that the gene expression of Bekos represents biomarkers which can be tracked over time and in response to treatment with EV. The loss of nectin-4 expression cells would alter the gene expression profile of the sample as the relative abundance of normal cells would increase and the relative abundance of nectin-4 expression cells would decrease. The ordinary artisan would be able to monitor the expression of the genes before, during and after treatment to determine whether nectin-4 expressing cells are present in a sample.
The Remarks argue it was the Applicants' discovery, which is provided in the instant specification, that administration of the "ADC comprising an anti-nectin-4 antibody or antigen binding fragment thereof conjugated to one or more units of MMAE via a linker" comprising the particular CDR's recited in Applicants' claims correlated with an increase in the "one or more ADC Set I Marker genes" recited in the instant claims (p. 24).
The prior art may suggest the claimed method despite doing so for a different purpose. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See MPEP 2144.IV. There is no argument that the EV ADC of Bekos is structurally different from those utilized in the claimed methods.
The Remarks summarize how applicant arrived at the claimed methods (p. 34).
The summary has been considered but it not pertinent as to the arguments of why Bekos does not render the claimed method obvious. Further, there is no evidence that the EV Bekos established to be known for treating nectin-4 positive cancers is any different from the genus of antibodies encompassed by the claimed methods. This is further supported by the fact that the instant specification used EV in their experiments.
The Remarks argue Satpayev does not cure the deficiencies of Bekos (p. 35).
It is the Examiner’s position that Bekos is not deficient for the reasons provided above.
The Remarks argue Adler does not cure the deficiencies of Bekos (p. 35-36).
It is the Examiner’s position that Bekos is not deficient for the reasons provided above.
The Remarks argue Lopez does not cure the deficiencies of Bekos (p. 36).
It is the Examiner’s position that Bekos is not deficient for the reasons provided above.
The Remarks argue Mar does not cure the deficiencies of Bekos (p. 37).
It is the Examiner’s position that Bekos is not deficient for the reasons provided above.
Conclusion
No claims allowed.
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 nonprovisional extension fee (37 CFR 1.17(a)) 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 mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOSEPH G DAUNER whose telephone number is (571)270-3574. The examiner can normally be reached 7 am EST to 4:30 EST with second Fridays Off.
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, Wu-Cheng Winston Shen can be reached at 5712723157. 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.
/JOSEPH G. DAUNER/ Primary Examiner, Art Unit 1682
Prosecution Insights