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 November 25, 2025 to the restriction requirement of August 26, 2025 has been received. Applicant has elected for examination the species of:
A. gene signature consisting of the expression of six to 10 genes selected from: SERPINH1, NOTCH2, FCGHR3 A/B, FPR1, FBP1, PDGFA, CRABP2, THBS1, ICOS, and CD8B;
B. comparing gene signature expression to (1) an individual who is suffering from said hematology malignancy or of a population of such individuals; and
C. CD123xCD3 antibody JNJ-63709178.
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 1-3, 5-17, 20-22, and 24 are pending and being examined as drawn to the elected species.
Specification
2. The incorporation of essential material in the specification by reference to an unpublished U.S. application, foreign application or patent, or to a publication is improper.
The instant specification discloses “JNJ-63709178” and “APVO436” antibodies that are essential material to the invention as recited in claim 17. The published specification at paragraphs [179-180], [183-184], and the last paragraph of the specification all incorporate by reference non-patent literature publications and WIPO documents to describe the “JNJ-63709178” and “APVO436” antibodies.
Applicant is required to amend the disclosure to include the material incorporated by reference, if the material is relied upon to overcome any objection, rejection, or other requirement imposed by the Office. The amendment must be accompanied by a statement executed by the applicant, or a practitioner representing the applicant, stating that the material being inserted is the material previously incorporated by reference and that the amendment contains no new matter. 37 CFR 1.57(g).
See the related rejection below in section 7.
Claim Objections
3. Claim 1 is objected to because of the following informalities: Claim 1 contains a typo. The gene “SERPHINH1” should be corrected to “SERPINH1”. Appropriate correction is required.
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.
4. Claims 1-3, 5-17, 20-22, and 24 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 1 recites the limitation "such individuals listed in (i)-(iii) above". There is insufficient antecedent basis for this limitation in the claim because claim 1 lists individuals in (1)-(3) above. Dependent claims are rejected for encompassing the rejected limitation o claim 1.
5. Claim 5 recites the limitation "the relative expression level of said gene expression signature in said population". There is insufficient antecedent basis for this limitation in the claim because no expression level of a population has been identified previously as the relative expression level.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
6. Claims 1-3, 5-17, 20-22, and 24 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature/ a natural phenomenon) without significantly more. The claim(s) recite(s) evaluating the expression of a gene expression signature consisting of six to ten genes selected from SERPINH1, NOTCH2, FCGHR3 A/B, FPR1, FBP1, PDGFA, CRABP2, THBS1, ICOS, and CD8B in a cellular sample from a patient having a hematological malignancy prior to treatment with a CD123 x CD3 bispecific molecule, comparing the gene expression signature to the gene expression signature of an individual or population of individuals suffering from said hematologic malignancy, and identifying the patients as a suitable responder for treatment with the CD123 x CD3 bispecific molecule if the expression of said gene expression signature is found to be increased relative to said expression of said gene expression signature of the individual or population of individuals. Thus, the claims are directed to the judicial exception of gene expression correlated to response to treatment with a CD123 x CD3 bispecific molecule.
This judicial exception is not integrated into a practical application because the claims recite only the detection or observation of a naturally occurring phenomenon/law of nature, which is data gathering to observe the naturally occurring phenomenon/law of nature without applying the data to a practical application. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims recite general detection procedures to evaluate and observe naturally occurring gene expression levels. The steps of evaluating the expression of 6 to 10 genes selected from SERPINH1, NOTCH2, FCGHR3 A/B, FPR1, FBP1, PDGFA, CRABP2, THBS1, ICOS, and CD8B in a patient having hematological cancer, as well as correlating to therapeutic responses, are considered known, routine steps and are typically taken by those in the field to perform testing of a sample and are not elements that are sufficient to amount to significantly more than the judicial exception (see MPEP 2106.05(d)). For example, McWeeney et al (Blood (2007) 110 (11) : 1007); Prince et al (Blood (2006) 108 (11) : 2715); Yan et al (Oncotarget, 2017, 8:1529-1540); and Boer et al (Haematologica, 2015, 100:e263) all teach and demonstrate utilizing commercially available Affymetrix U133 Plus 2.0 array to detect gene expression levels in hematologic cancer patients for comparison and correlation to therapeutic responses, wherein Affymetrix U133 Plus 2.0 array comprises detection of all of SERPINH1, NOTCH2, FCGHR3 A/B, FPR1, FBP1, PDGFA, CRABP2, THBS1, ICOS, and CD8B genes, as well as ABCF1 (Affymetrix HG-U133 Plus 2.0 annotation files are located at https://www.thermofisher.com/order/catalog/product/900466). US Patent Application Publication 2021/0395374, Davidson et al; Rutella et al (Blood, November 2018, 132(Supplement 1):444); Uy et al (Blood, November 2018; 132(Supplement 1):764); Uy et al (Blood, November 2019; 134 (Supplement 1):733); and Vadakekolathu et al (Blood, November 2019, 134 (Supplement 1): 460) all demonstrate utilizing commercially available Nanostring PanCancer IO360™ array to detect gene expression levels in hematologic cancer patients for comparison and correlation to therapeutic responses to CD123xCD3 bispecific molecule treatment, wherein Nanostring PanCancer IO360™ array comprises detection of all of SERPINH1, NOTCH2, FCGHR3 A/B, FPR1, FBP1, PDGFA, CRABP2, THBS1, ICOS, and CD8B, as well as ABCF1 (see attached list of genes detected by PanCancer IO360™ array from https://nanostring.com/resources/pancancer-human-io360-panel-gene-list/). Routine data gathering in order to observe a natural phenomenon/ natural principle does not add a meaningful limitation to the method as it would be routinely used by those of ordinary skill in the art in order to observe the natural phenomenon/ natural principle, and it fails to narrow the scope of the claims such that others are not foreclosed from using the law of nature/natural phenomenon. Methods of detecting natural phenomenon preempt all practical uses of it as others must use/detect the natural phenomenon to apply it to any other correlations, diagnosis, prognosis, therapeutic response, monitoring, etc.
Claims 7 and 8 recite the method further comprises administering a treatment dosage of said CD123 x CD3 bispecific molecule to said patient if the patient is determined to be a suitable responder to such treatment. Claims 7 and 8 do not recite a practical application of the judicial exception because the claims do not require definitively identifying the patient as a suitable responder to such treatment and administering said CD123 x CD3 bispecific molecule to said patient identified patient. The claims state that CD123 x CD3 bispecific molecule is only administered if the patient is determined to be a suitable responder to such treatment and no such determination was made in the claimed method. Therefore, the step of practically applying the judicial exception by administering said CD123 x CD3 bispecific molecule is not required for the claimed method.
To obviate the rejection, there must be at least one additional element or physical step that applies, relies on, or uses the natural principle so that the claim amounts to significantly more than the judicial exception itself. The claimed method currently fails to provide a practical application of the judicial exception and fails to add any elements that amount to significantly more than the judicial exception.
Examiner Suggestion: Amend claim 1 to recite:
“…
(b) detecting an increased expression of said gene expression signature from the patient relative to said expression of said gene expression signature of the individual or population of such individuals listed in (1)-(3);
(c) identifying the patient as a suitable responder for treatment with a CD123 x CD3 bispecific molecule; and
(d) administering said CD123 x CD3 bispecific molecule to the patient;
wherein said gene expression signature consists of the expression of from six to ten genes selected from: SERPINH1, NOTCH2, FCGR3 A/B, FRP1, FBP1, PDGFA, CRABP2, THBS1, ICOS, and CD8B.”
7. Claim 17 is 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-AlA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The invention appears to employ novel biological materials, specifically JNJ-63709178, XmAb14045, and APVO436 as recited in claim 17.
Claim 17 is rejected as failing to provide an adequate written description of the invention, because the specification does not provide evidence that the claimed biological materials are (1) known and readily available to the public; (2) reproducible from a written description (e.g. sequenced); or (3) deposited.
Since the biological materials are essential to the claimed invention they must be obtainable by a repeatable method set forth in the specification or otherwise readily available to the public. If the biological materials are not so obtainable or available, the requirements of 35 U.S.C. 112 may be satisfied by a deposit of the biological materials. The specification does not disclose a repeatable process to obtain the biological materials and it is not apparent if the biological materials are readily available to the public. It is noted that the instant specification discloses:
[0178] II. Exemplary CD123×CD3 Bispecific Binding Molecules
[0179] A. JNJ-63709178
[0180] JNJ-63709178 is a humanized IgG4 bispecific antibody with silenced Fc function. The antibody was produced using Genmab DuoBody® technology and is able to bind both CD123 on tumor cells and CD3 on T cells. JNJ-63709178 is able to recruit T cells to CD123-expressing tumor cells and induce the killing of these tumor cells in vitro (MOLM-13, OCI-AML5 and KG-1; EC50=0.51−0.91 nM). JNJ-63709178 is disclosed in WO 2016/036937, Gaudet, F. et al. (2016) “Development of a CD123×CD3 Bispecific Antibody (JNJ-63709178) for the Treatment of Acute Myeloid Leukemia (AML),” Blood 128:2824; and Forslund, A. et al. (2016) “Ex Vivo Activity Profile of the CD123×CD3 Duobody® Antibody JNJ-63709178 Against Primary Acute Myeloid Leukemia Bone Marrow Samples,” Blood 128:2875, which documents are herein incorporated by reference). The amino acid sequences of the heavy and light chains of JNJ-63709178 and/or related antibodies: 13RB179, 13RB180, 13RB181, 13RB182, 13RB183, 13RB186, 13RB187, 13RB188, 13RB189, CD3B19, 7959, 3978, 7955, 9958, 8747, 8876, 4435 and 5466 are disclosed in WO 2016/036937.
[0181] B. XmAb14045
[0182] XmAb14045 (also known as vibecotamab) is a tumor-targeted antibody that contains both a CD123 binding domain and a cytotoxic T-cell binding domain (CD3). An XmAb Bispecific Fc domain serves as the scaffold for these two antigen binding domains and confers long circulating half-life, stability and ease of manufacture on XmAb14045. Engagement of CD3 by XmAb14045 activates T cells for highly potent and targeted killing of CD123-expressing tumor cells (US Patent Publication 2017/0349660; Chu, S. Y. et al. (2014) “Immunotherapy with Long-Lived Anti-CD123× CD3 Bispecific Antibodies Stimulates Potent T Cell-Mediated Killing of Human AML Cell Lines and of CD123+ Cells in Monkeys: A Potential Therapy for Acute Myelogenous Leukemia,” Blood 124(21):2316, which documents are herein incorporated by reference). The amino acid sequences of the heavy and light chains of XmAb14045 and similar CD123×CD3 bispecific binding molecules are disclosed in US Patent Publication 2017/0349660 and in WHO Drug Information, Proposed INN: List 120, 2018, 32(4):658-660.
[0183] C. APVO436
[0184] APVO436 is an ADAPTIR™ CD123×CD3 bispecific binding molecule that possesses an anti-CD123 scFv portion and an anti-CD3 scFv portion. Each of the scFv portions are bound to an Fc Domain that has been modified to abolish ADCC/CDC effector function. APVO436 is disclosed to bind human CD123 and CD3-expressing cells with EC50 values in the low nM range and to demonstrate potent target-specific activity against CD123-expressing tumor cell lines at low effector to target ratios. APVO436 is disclosed to be capable of potently inducing endogenous T-cell activation and proliferation accompanied by depletion of CD123 expressing cells in experiments with primary AML subject samples and normal donor samples. APVO436 (see, Comeau, M. R. et al. (2018) “APVO436, a Bispecific anti-CD123×anti-CD3 ADAPTIR™ Molecule for Redirected T-cell Cytotoxicity, Induces Potent T-cell Activation, Proliferation and Cytotoxicity with Limited Cytokine Release,” AACR Annual Meeting April 2018, Abstract 1786; Godwin, C. D. et al. (2017) “Bispecific Anti-CD123×Anti-CD3 ADAPTIR™ Molecules APVO436 andAPVO437Have Broad Activity Against Primary Human AML Cells In Vitro,” American Society of Hematology Annual Meeting, December 2017, Blood 130:2639; Comeau, M. R. et al. (2017) “Bispecific anti-CD123×anti-CD3 ADAPTIR™ Molecules for Redirected T-cell Cytotoxicity in Hematological Malignancies,” AACR Annual Meeting April 2017, Abstract 597). The amino acid sequences of the heavy and light chains of APVO436 CD123×CD3 bispecific binding molecules are disclosed in WO 2018/057802A1.
With regard to JNJ-63709178, a humanized IgG4 bispecific antibody, the instant specification fails to disclose the sequence of the antibody and its public availability. Although the specification discloses the antibody is discussed in non-patent literature and the amino acid sequences of the heavy and light chains of JNJ-63709178 and/or related antibodies are disclosed in WO 2016/03693, CFR 37 § 1.57 states that essential material critical to satisfying the written description requirement cannot be met by incorporating by reference non-patent literature or foreign applications (see below). Further, it does not appear that the sequences of JNJ-63709178 are disclosed in the non-patent literature and there is no mention of “JNJ-63709178” in WO 2016/036937.
With regard to XmAb14045, the written description requirement is met because the instant specification incorporates by reference US Patent Publication 2017/0349660 that discloses the sequences of the antibody.
With regard to APVO436, an ADAPTIR™ CD123×CD3 bispecific binding molecule that possesses an anti-CD123 scFv portion and an anti-CD3 scFv portion, the instant specification fails to disclose the sequence of the antibody and its public availability. Although the specification discloses APVO436 is mentioned in non-patent literature and the amino acid sequences of the heavy and light chains of APVO436 CD123×CD3 bispecific binding molecules are disclosed in WO 2018/057802A1, CFR 37 § 1.57 states that essential material critical to satisfying the written description requirement cannot be met by incorporating by reference non-patent literature and foreign applications (see below). Further, it does not appear that the sequences of APVO436 are disclosed in the non-patent literature and there is no mention of “APVO436” in WO 2018/057802A1.
The instant specification cannot incorporate by reference non-patent literature and foreign patent applications to provide written descriptive support for essential material, such as the antibodies listed above. CFR 37 § 1.57 states:
(c) “Essential material” may be incorporated by reference, but only by way of an incorporation by reference to a U.S. patent or U.S. patent application publication, which patent or patent application publication does not itself incorporate such essential material by reference. “Essential material” is material that is necessary to:
(1) Provide a written description of the claimed 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 set forth the best mode contemplated by the inventor of carrying out the invention as required by the first paragraph of 35 U.S.C. 112;
(2) Describe the claimed invention in terms that particularly point out and distinctly claim the invention as required by the second paragraph of 35 U.S.C. 112; or
(3) Describe the structure, material, or acts that correspond to a claimed means or step for performing a specified function as required by the sixth paragraph of 35 U.S.C. 112.
In the instant case, the specification does not disclose the structure of the claimed JNJ-63709178 and APVO436 antibodies, and does not provide any information on public availability of the antibodies in terms of commercial sale or by publicly available sequences.
8. Conclusion: No claim is allowed. The closest prior art made of record but not relied upon is US Patent Application Publication 2021/0395374, Davidson et al, claiming priority to October and November 2018. Davidson teaches a method of determining whether a patient would be a suitable responder to the use of CD123 x CD3 bispecific molecule to treat a hematological malignancy, wherein said method comprises:
(a) evaluating the expression of a gene expression signature in a bone marrow sample from the patient prior to the administration of the CD123 x CD3 bispecific molecule, wherein evaluating gene expression used PanCancer IO360™ assay that includes SERPINH1, NOTCH2, FCGR3 A/B, FRP1, FBP1, PDGFA, CRABP2, THBS1, ICOS, and CD8B genes and reference gene ABCF1 (see Tables 2 and 3; [230-238]);
(b) comparing the patient gene expression levels in the gene expression signature to levels of the genes expressed in an individual or population of individuals who have the same hematological malignancy;
(c) correlating gene expression level in the patient with response to CD123 x CD3 bispecific molecule to identify a suitable responder; and
(d) administering said CD123 x CD3 bispecific molecule to the patient;
wherein the CD123 x CD3 bispecific molecule is JNJ-63709178 ([242-243]);
wherein the patient has AML; and
wherein the patient is chemotherapy refractory (for entire method, see abstract; [21-134]; claims 1-31).
Davidson does not identify any subset of 6 to 10 genes selected from SERPINH1, NOTCH2, FCGR3 A/B, FRP1, FBP1, PDGFA, CRABP2, THBS1, ICOS, and CD8B that identify a patient as being a suitable responder to CD123 x CD3 bispecific molecule treatment when their expression is increased relative to individuals who have the same malignancy, nor does Davidson teach or suggest treating this patient population. Therefore, Davidson does not teach or suggest the claimed method..
9. 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