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 .
1. The response filed on September 8, 2025 to the restriction requirement of July 8, 2025 has been received. Applicant has elected for examination Group I, and the species of:
A. antibody; and
B. antibody comprising CDR SEQ ID NOs:21+26+31; 36+41+46; and SEQ ID NOs:8 and 9.
Because Applicant did not distinctly and specifically point out any errors in the restriction requirement, the election has been treated as an election without traverse (MPEP 818.03(a)).
Claims 1-19 are pending. Claims 12-16, 18, and 19 have been withdrawn from further consideration by the examiner under 35 CFR 1.142(b) as being drawn to non-elected inventions. All species have been rejoined for examination. Claims 1-11 and 17 are currently under prosecution.
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.
2. Claim 5 is 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.
Claim 5 recites: “a. said LCDR1 is comprise in, particularly is identical to an LCDR1 reference sequence selected from SEQ ID NO 020, SEQ ID NO 021…”
This language is repeated in parts b. -f. of claim 5.
Claim 5 also recites: “particularly said HCDR2 is comprised in, particularly identical to…” in part e.
The scope of the claimed LCDR and HCDR claimed is unclear. The language in bold font above simultaneously identifies the CDR as “comprised in” and “identical to” the SEQ ID NOs. A sequence can be comprised within a SEQ ID NO but not be identical to the SEQ ID NO itself, so it is unclear what the claimed requirements are for the CDR sequences comprised by the antibody.
Examiner suggestion: Amend claim 5 to recite: “a. said LCDR1 is identical to an LCDR1 reference sequence selected from SEQ ID NO 020, SEQ ID NO 021, …and SEQ ID NO 024;” and amend sections b. – f. to recite the same language.
3. Claim 5 is further 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.
Claim 5 recites the term “particularly” as stated above.
Claim 5 also recites at the end of the claim: “particularly wherein at most two amino acids are exchanged, more particularly wherein at most one amino acid is exchanged by the substitution rules given above.”
The phrase "particularly" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Examiner suggestion: Delete the term “particularly”.
4. Claim 3, 6, 8, and 9 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.
Claim 3 recites “particularly wherein said non-agonist…”
Claim 6 recites in sections a. and e. “particularly said LCDR2 is selected from SEQ ID NO…” or “particularly said HCDR2 is selected from SEQ ID NO…”
Claims 8 and 9 recite “particularly ≥94%, ≥96% or even ≥98% identical to…” in sections a. and b.
The phrases "particularly" and “or even” render the claims indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
5. Claim 7 is 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.
Claim 7 recites: “The method of claim 4, comprising a. said LCDR1 is of sequence SEQ ID NO 020, said LCDR2 is of sequence SEQ ID NO 050, said LCDR3 is of sequence SEQ ID NO 030, said HCDR1 is of sequence SEQ ID NO 035, said HCDR2 is of sequence SEQ ID NO040 or SEQ ID NO 055, and said HCDR3 is of sequence SEQ ID NO 045, …” Sections b. – e. of claim 7 comprise similar language.
The phrase “is of sequence SEQ ID NO” renders the claim unclear with regard to the relationship of the CDRs to the SEQ ID NOs. Does the phrase “is of sequence SEQ ID NO” mean the CDR is comprised in the SEQ ID NO, or does it mean the CDR is identical to the SEQ ID NO, or does it mean something else? Clarification is required.
6. Claims 7-9 are further 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.
Claim 7 recites: “The method of claim 4, comprising a. said LCDR1 is of sequence SEQ ID NO 020…”
Claim 8 recites: “The method of claim 4, comprising a. a first sequence at least 90% identical,…”
Claim 9 recites: “The method of claim 4, comprising a sequence at least 90% identical…”
The claims are unclear with regard to what in the method comprises said LCDR1, a first sequence, or a sequence. The method does not comprise these CDRs or sequence, but rather, it appears the antibody or antibody-like molecule does.
Examiner suggests clarifying the claim limitations by amending claims to recite language such as: “The method of claim 4, wherein the antibody or antibody-like molecule comprises…”
7. Claim 11 is 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.
Claim 11 recites: “The method of claim 4 characterized in that it is specifically reactive against a polypeptide encoded by any one of SEQ ID NO…”
The claim is unclear with regard to what “it” is that the claim is referring to. There is insufficient antecedent basis for this limitation in the claim.
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.
8. Claim 5 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 5 encompasses a vast range of variant substituted CDR sequences outside the scope of the CDR sequences limited in claim 4.
Claim 5 depends on claim 4. Claim 4 is limited to an antibody or antibody-like molecule comprising LCDR1, LCDR2, LCDR3, HCDR1, HCDR2, and HCDR3 sequences that are comprised in the light and heavy chain SEQ ID NOs listed in a.-f.
The instant specification defines the LCDR1, LCDR2, LCDR3, HCDR1, HCDR2, and HCDR3 sequences found in the light and heavy chain SEQ ID NOs recited in claim 4. For example, Table 1 lists the heavy and light chain sequences that are recited in claim 4:
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244
320
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Table 2 identifies the LCDR1, LCDR2, LCDR3, HCDR1, HCDR2, and HCDR3 sequences comprised in the light and heavy chain SEQ ID NOs recited in claim 4:
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194
302
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356
314
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358
320
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Therefore, claim 4 limits the CDRs of the antibody and antibody-like molecule to the CDR sequences comprised in the recited heavy and light chain SEQ ID NOs.
Claim 5 recites that that LCDR1, LCDR2, LCDR3, HCDR1, HCDR2, and HCDR3 are “derived from” the recited CDR SEQ ID NOs “by the substitution rules given below”, wherein the substitution rules recited allow for several amino acid substitutions within the recited CDR SEQ ID NOs. Therefore, claim 5 encompasses a vast range of variant substitution CDR sequences outside the scope of the CDR sequences limited in claim 4.
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.
Examiner Suggestion: Delete the phrases in sections a. – f. reciting “or wherein said [L/H]CDR[#] is derived from any one of said [L/H]CDR[#] reference sequences by the substitution rules given below” and delete the entire last claimed section of “and wherein the substitution rules for deriving said LCDR1, LCDR2, LCDR3, HCDR1, HCDR2, and HCDR3 sequence from their respective reference sequences are:…”
Given the scope of the antibody and antibody-like molecules recited in claim 5 is outside the scope of those recited in claim 4, claim 5 is rejected under 35 USC 112(a) written description below, while claim 4 is not.
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.
9. Claims 1-3, 5, and 17 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. This is a WRITTEN DESCRIPTION rejection.
The claims are drawn to a method for treating cancer, comprising: administering to a subject in need thereof a non-agonist ligand of ARTC1, thereby treating the cancer (claim 1); wherein said ligand inhibits the ADP-ribosyltranferase activity of ARTC1 (claim 2); wherein the ligand is selected from an antibody, antibody-like molecule, an aptamer, an antibody fragment, particularly wherein said non-agonist ligand is selected form an antibody and an antibody like molecule (claim 3); characterized in being able to prevent ADP-ribosylation of RR, RG, GR, RXR, and GXXXXR motifs (claim 10); and wherein it is specifically reactive against a polypeptide encoded by any one of SEQ ID NO 1-4 (claim 11).
Thus, the claims require using a non-agonist ligand of ARTC1 defined only by function of:
Treat cancer;
Binds ARTC1 (ligand);
Non-agonist of ARTC1; and
inhibits the ADP-ribosyltranferase activity of ARTC1;
prevents ADP-ribosylation of RR, RG, GR, RXR, and GXXXXR motifs; and
is specifically reactive against a polypeptide encoded by any one of SEQ ID NO 1, 2, 3, or 4.
No structure is recited. The claimed ligand is critical to practicing the claimed method.
Claim 5 recites the antibody or antibody-like molecule comprises CDRs “derived from” the listed CDR SEQ ID NOs having any of the amino acid substitutions according to substitution rules recited in claim 5. Therefore, claim 5 provides a partial structure, encompassing a vast genus of variant antibodies or antibody-like molecules comprising any number of amino acid substitutions anywhere in the CDR sequences as defined by the substitution rules of claim 5.
The instant specification discloses anti-ARTC1 rat antibodies RG4-A111, R19-A3, R17254-A271, R17254-A327, and R17254-A197 and their defined light chain, heavy chain, and six CDR sequences (see Tables 1 and 2).
The specification discloses anti-human ARTC1 antibody HA003ximo2a is the VH and VL domains of the original rat A3 clone fused to murine IgG2a/K constant regions (Example 4). The specification discloses utilizing antibody HA003ximo2a and rat A3 fused to a rabbit IgG-Fc in the examples to treat mice comprising tumors transfected to express human ARTC1, wherein the antibodies block enzymatic function of ARTC1 (Figures 2-3). The specification discloses the anti-tumor function of the HA003ximo2a antibody is 2-fold: (1) inhibition of ADP-ribosylation and (2) antibody-dependent cellular cytotoxicity (ADCC) (Example 5). The specification discloses: (Example 5) The inventors identified ADP-ribosylated proteins that are involved in tumor growth (growth factor and receptors), vascularization, metastasis and immune regulation (cytokines and their receptors). Furthermore, upon antibody treatment or shRNA knockdown, these proteins are not ADP-ribosylated anymore.
The specification further discloses rat antibody clone A197 was recombinantly produced in the form of rat-mouse chimeric antibody and was named MA197ximo2a (Figure 5; [145]). MA197ximo2a was administered to mice comprising tumors expressing ARTC1 and reduced tumor volume compared to control PBS (Figure 5; Example 5).
Thus, the instant specification describes five rat monoclonal anti-ARTC1 antibodies that treat cancer and neutralize ADP-ribosyltransferase activity of ARTC1 as claimed, wherein the five antibodies comprise six defined CDR sequences critical to their ARTC1 binding and anti-cancer function. The specification fails to disclose any other ligands, antibodies, antibody-like molecules, and aptamers, that possess the functions claimed and listed above.
In relevant art, ARTC1 ligands having neutralizing activity that treat cancer are not well known, particularly antibodies, antibody-like molecules, and aptamers. Tang et al (International Journal of Molecular Medicine, 2013, 32:130-136) teaches knockdown of ART1 (synonym of ARTC1) expression in colorectal cancer cells with a shRNA lentivirus, and teach inhibiting ART1 activity with ligand meta-iodobenzylguanidine (MIBG), a small molecule that binds to the catalytic site of ART1. However, Tang does not disclose any antibodies, antibody-like molecules, or aptamers that function claimed. Su et al (International Journal of Molecular Medicine, 2014, 34:842-848) teaches meta-iodobenzylguanidine (MIBG), a small molecule that binds to the catalytic site of ART1, has anti-tumor function against hepatocellular carcinoma cells (abstract; Introduction) and teaches it was previously demonstrated that gene silencing of ART1 in colorectal carcinoma cells had anti-tumor effects (Introduction), but does not disclose any antibodies, antibody-like molecules, or aptamers that function claimed. McCluskey et al (Clinical Cancer Research, 2005, 11:7929-7937) teaches treatment of cancer patients by administering [131I]MIBG, but does not disclose any antibodies, antibody-like molecules, or aptamers that function claimed. Therefore, it appears that non-agonist ligands of ARTC1, particularly antibodies, antibody-like molecules, and aptamers, for the treatment of cancer are not well-known or established in the art at the time the application was effectively filed.
To provide adequate written description and evidence of possession of the claimed ligand genus, the instant specification can structurally describe representative ligands, antibodies, antibody-like molecules, and aptamers that function as claimed and listed above, or describe structural features common to the members of the genus, which features constitute a substantial portion of the genus. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics (see University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc.). A disclosure that does not adequately describe a product itself logically cannot adequately describe a method of using that product.
Although Applicants may argue that it is possible to screen for ligands that bind ARTC1 and function as claimed, the court found in (Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004) that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. “As we held in Lilly, “[a]n adequate written description of a DNA … ‘requires a precise definition, such as by structure, formula, chemical name, or physical properties,’ not a mere wish or plan for obtaining the claimed chemical invention.” 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions.” Knowledge of screening methods provides no information about the structure of any future ligands, antibodies, antibody-like molecules, and aptamers yet to be discovered that may function as claimed. The ARTC1 protein provides no information about the structure of ligands, antibodies, antibody-like molecules, and aptamers that bind to it.
In this case, the only factor present in the claims is a recitation of the ligand function as listed above. The instant specification fails to describe structural features common to the members of the genus, which features constitute a substantial portion of the genus because the instant specification discloses only five exemplary monoclonal antibody sequences that function as claimed. A definition by function does not suffice to define the genus because it is only an indication of what the ligand does, rather than what it is. Other than for the five antibodies listed in Tables 1 and 2, the specification fails to provide the structural features coupled to the claimed functional characteristics for the broadly claimed genus of ligands required to practice the method. The instant specification fails to describe a representative number of ligand sequences/structures for the genus of ligands that function as claimed. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus required to perform the claimed method.
In the instant case, the specification discloses the sequences of five exemplary rat anti-ARTC1 antibodies that function as claimed, wherein the antibodies comprise six defined CDRs (LCDRs1-3 and HCDRs1-3) that are critical to the ARTC1 binding and cancer-treating functions. The instant specification does not disclose which amino acid substitution variants can occur in these CDR sequences and still maintain the claimed functions, particularly relevant to instant claim 5. Applicants have not established any reasonable structure-function correlation with regards to the sequences in the CDRs that can be altered and still maintain the claimed functions. The instant specification does not describe representative examples to support the full scope of the claimed ligands and antibody variants because the instant specification discloses the sequence structure of only five rat monoclonal antibodies to ARCTC1 that function as claimed. Given the well-known high level of polymorphism of antibody CDR sequences and structure, the skilled artisan would not have been in possession of the vast repertoire of antibodies and antibody variants encompassed by the claimed invention. One could not reasonably or predictably extrapolate the structure of five rat monoclonal anti-ARTC1 antibodies to the structure of any and all anti-ARTC1 ligands, antibodies, antibody-like molecules, or aptamers as broadly claimed in the methods. Therefore, one could not readily envision members of the broadly claimed genus required to practice the claimed method.
Given the lack of representative examples to support the full scope of the claimed ligands, aptamers, and antibody/ antibody-like sequence variants used in the claimed method, and lack of reasonable structure-function correlation with regards to the unknown sequences/structures in the ligands, aptamers, antibodies, antibody-like molecules, or CDRs that provide the claimed functions, the present claims lack adequate written description. Thus, the specification does not provide an adequate written description of non-agonist ligands of ARTC1 that is required to practice the claimed invention. Since the specification fails to adequately describe the product to which the claimed method uses, it also fails to adequately describe the method.
Examiner Suggestion: Amend claim 1 to recite and require the non-agonist ligand of ARTC1 to comprise, at minimum, six defined LCDR1, LCDR2, LCDR3, HCDR1, HCDR2, and HCDR3 SEQ ID NOs from the antibody sequences listed in Tables 1 and 2.
10. Claims 1-11 and 17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating cancer expressing ARTC1 in a subject, the method comprising administering to the subject an anti-ARTC1 antibody comprising a light chain variable region comprising LCDR1, LCDR2, LCDR3, and a heavy chain variable region comprising HCDR1, HCDR2, and HCDR3; wherein LCDR1 comprises the CDR1 sequence selected from the group consisting of SEQ ID NOs:20, 21, 22, 23, and 24; LCDR2 comprises the CDR2 sequence selected from the group consisting of SEQ ID NOs:25, 26, 27, 28, and 29; LCDR3 comprises the CDR3 sequence selected from the group consisting of SEQ ID NOs:30, 31, 32, 33, and 34; HCDR1 comprises the CDR1 sequence selected from the group consisting of SEQ ID NOs:35, 36, 37, 38, and 39; HCDR2 comprises the HCDR2 sequence selected from the group consisting of SEQ ID NOs:40, 41, 42, 43, 44, 55, 56, 57, 58, and 59; and the HCDR3 comprises the CDR3 sequence selected from the group consisting of SEQ ID NOs:45, 46, 47, 48, and 49;
does not reasonably provide enablement for treating any cancer in a subject that does not express ARTC1, treating a subject that does not even have cancer yet, and treating the subject with any non-agonist ligand of ARTC1 as broadly claimed. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue,' not 'experimentation.' " (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.
The claims broadly encompass: (a) treating subjects who do not have cancer yet (claim 17), (b) subjects having cancer that do not express ARTC1 (claim 1); and (c) administering to the subject any non-agonist ligand of ARTC1.
As stated and summarized in the written description rejection above, the instant specification discloses five rat anti-ARTC1 antibodies that function to neutralize ARTC1 enzymatic activity and treat cancer. The instant specification discloses in Example 1, detecting ARTC1 expression in cancers: breast, colon, lung, liver, glioma, kidney, testis, pancreas, sarcoma, melanoma, and prostate cancer. Cancer patients having ARTC1 expression had reduced survival (Figure 1, Example 1).
The specification discloses:
Example 4: Treatment Data
[0158] To show that ARTC1 is a therapeutic target in human cancers, the inventors established in vivo cancer models of human cancer cell lines grown in CB17-Scid mice. As for the moment, the inventors have not yet identified established cancer cell lines that express detectable ARTC1 at the cell surface in vitro, thus, they transduced cell lines with full length human ARTC1 or as control with an shRNA to knockdown endogenous ARTC1. The human TNBC cell line MDA-MB-231 (0.5 Mio) were injected orthotopically into the mammary fat pads. Starting from day 7 after tumor inoculation, the treatment group received twice weekly by intraperitoneal injection 15 mg/kg of the enzyme-neutralizing anti-human ARTC1 antibody HA003ximo2a (VH and VL domains of the original rat A3 clone were fused to murine IgG2a/K constant regions). The data shows that with an antibody treatment targeted to extracellular ARTC1, the tumor growth can be reduced as efficiently as with ARTC1 knock-down (FIG. 3A). This data shows that patients can be treated by a therapy targeted to ARTC1 either by an antibody, RNA interference or a small molecule inhibitor.
[0159] In another experimental setting, the inventors treated with twice weekly 5 mg/kg anti-human ARTC1 antibody HA003ximo2a and obtained a nearly as pronounced treatment effect as with 15 mg/kg (data not shown).
[0160] In another treatment experiment, human lung adenocarcinoma A549 cells (1 Mio) were injected s.c. into the flanks of CB17-Scid mice. Starting from day 7 after tumor inoculation, the treatment group received once weekly by intraperitoneal injection 3 mg/kg of the enzyme-neutralizing anti-human ARTC1 antibody HA003ximo2a (FIG. 3B). A second group received once weekly a scFv version of rat A3 fused to a rabbit IgG-Fc in a molar amount equivalent to 6.75 mg/kg of a full IgG antibody. The data shows that a treatment with 3 mg/kg antibody once weekly had no effect, while an equivalence dose of 6.75 mg/kg already slightly delayed tumor growth.
[0162] In another treatment experiment, human A549 lung or SW620 colon carcinoma cells, respectively, were injected subcutaneously in CB17-Scid mice and animals were treated from day 7 on with 15 mg/kg HA003ximo2a i.p. twice weekly (FIGS. 5A and 5B).
[0163] In another treatment experiment, murine syngeneic 4T1 breast cancer cells were injected orthotopically into BALB/c mice and animals were treated from day 7 on with 15 mg/kg MA197ximo2a i.p. twice weekly (FIG. 5C). The results show that the ARTC1-targeted treatment also works in a fully syngeneic system and in the presence of a full immune system.
[0164] In another treatment experiment, murine syngeneic MC38 colon carcinoma cells were injected i.v. in wildtype C57BL/6 animals and animals were treated from day 0 on with 15 mg/kg MA197ximo2a i.p. twice weekly (FIG. 5D). Lungs were harvested on day 21 and treated with Bouin's solution. Metastases nodules (not shown) and lung weights were determined. These experiments revealed that ARTC1 contributes to disease severity by enhancing metastatic seeding. Antibody treatment led to a reduction of metastatic burden.
Thus, the instant specification discloses having to create cell lines expressing ARTC1 for treatment experiments by transfecting ARTC1 into the cells. The specification demonstrates that ARTC1 expression is required for tumors to be targeted by the anti-ARTC1 antibodies enabling treatment. The specification does not provide any working examples of predictably treating cancer in a subject that does not have cancer yet or that is at risk of developing cancer sometime in the future (i.e., prevention). The claims are not enabled for treating cancer that does not express the ARTC1 protein that is targeted by the claimed ligand. The claims are not enabled for treating cancer in a subject that does not even have cancer yet.
The specification discloses the two main functions of the antibodies that treated cancer are: (1) inhibition of ARTC1 ADP-ribosylation function, and (2) antibody-dependent cellular cytotoxicity (ADCC) (Example 5). The specification does not disclose any other ligands, antibodies, antibody-like molecules or aptamers that predictably treat cancer as claimed, nor does the specification disclose any methods for readily producing and identifying a non-agonist ligand that predictably functions as claimed. The state of the art at the time of effective filing was such that non-agonist ARTC1 ligands having neutralizing activity that treat cancer were not well known, particularly antibodies, antibody-like molecules, and aptamers. (see Tang, Su, and McCluskey teachings stated above in the written description rejection). A high quantity of experimentation would be required to produce and screen for a ligand that predictably functions as claimed.
Therefore, in view of the novel nature of the invention, the state of the art, the quantity of experimentation necessary, the breadth of the claims, lack of guidance in the specification for predictably making and using non-agonist ARTC1 ligands that function as claimed, it would require undue experimentation for one skilled in the art to practice the invention as broadly claimed.
Examiner Suggestion: Amend claim 1 to recite: A method for treating cancer in a subject, the method comprising administering to the subject an anti-ARTC1 antibody comprising a light chain variable region comprising LCDR1, LCDR2, LCDR3, and a heavy chain variable region comprising HCDR1, HCDR2, and HCDR3; wherein
the LCDR1 is a CDR1 comprised in a light chain variable region sequence
selected from SEQ ID NO 006, SEQ ID NO 009, SEQ ID NO 012, SEQ ID NO 015 and SEQ ID NO 018;
b. the LCDR2 is a CDR2 comprised in a light chain variable region sequence selected from SEQ ID NO 006, SEQ ID NO 009, SEQ ID NO 012, SEQ ID NO 015 and SEQ ID NO 018;
c. the LCDR3 is a CDR3 comprised in a light chain variable region sequence selected from SEQ ID NO 006, SEQ ID NO 009, SEQ ID NO 012, SEQ ID NO 015 and SEQ ID NO 018;
d. the HCDR1 is a CDR1 comprised in a heavy chain variable region sequence selected from SEQ ID NO 005, SEQ ID NO 008, SEQ ID NO 011, SEQ ID NO 014 and SEQ ID NO 017;
e. the HCDR2 is a CDR2 comprised in a heavy chain variable region sequence selected from SEQ ID NO 005, SEQ ID NO 008, SEQ ID NO 011, SEQ ID NO 014 and SEQ ID NO 017; and
f. the HCDR3 is a CDR3 comprised in a heavy chain variable region sequence selected from SEQ ID NO 005, SEQ ID NO 008, SEQ ID NO 011, SEQ ID NO 014 and SEQ ID NO 017.
Delete claim 17.
Claim Rejections - 35 USC § 102
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.
11. Claim(s) 1, 2, 10, 11, and 17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by McCluskey et al (Clinical Cancer Research, 2005, 11:7929-7937), as evidenced by Su et al (International Journal of Molecular Medicine, 2014, 34:842-848) and Tang et al (International Journal of Molecular Medicine, 2013, 32:130-136).
McCluskey teaches treating cancer in a subject by administering to the subject [131I]meta-iodobenzylguanidine ([131I]MIBG) (Materials and Methods; p. 7932, col. 2 to p. 7933, col. 2; Figure 4; Table 1). Given the subjects treated in the method of McCluskey are diagnosed with cancer, they inherently have been assigned a high likelihood of having cancer, as required by claim 17.
As evidenced by Su, meta-iodobenzylguanidine (MIBG), is a small molecule that binds to the catalytic site of human ART1 (p. 842, col. 2). As evidenced by Tang, meta-iodobenzylguanidine (MIBG), is a potent inhibitor of arginine-specific mono-ADP-ribosyltransferases and to inhibits the ADP-ribosylation activity of ART1 (p. 131, col. 1). Therefore, the MIBG administered to cancer patients in the method of McCluskey is inherently a non-agonist ligand of human ARTC1 that inhibits the ADP-ribosyltransferase activity of ARTC1 that acts on the claimed motifs (claim 10), and is reactive against human ARTC1 protein and its catalytic region encoded by the sequences recited in instant claim 11.
12. Conclusion: No claim is allowed.
13. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAURA B GODDARD whose telephone number is (571)272-8788. The examiner can normally be reached Mon-Fri, 7am-3:30pm.
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/Laura B Goddard/Primary Examiner, Art Unit 1642