DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
The following elections have been made:
On 10/19/2024, applicants elected Group II, claims 3-22 and 28, as well as species IFN Gamma Signaling signature (species election D). Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement dated 5/29/2024, the election has been treated as an election without traverse (MPEP § 818.01(a)). It is noted that the species election requirements A-C were withdrawn and species election requirements B and C were newly applied in the subsequent restriction requirement dated 2/10/2025.
On 8/8/2025, in response to newly applied species election requirement B, Applicants elected species CXCL9, CXCL10, CXCL11, and STAT1 without traverse (applicant did not distinctly and specifically point out the supposed errors in this requirement). In response to species election requirement C, applicant elected with traverse the combination of ABCG1, G6PD, and NRDE2. However, upon further search and review, species election requirement is withdrawn and the species listed in claim 14 are rejoined.
The remaining outstanding restriction and species election requirements, as detailed above, are still deemed proper and therefore made FINAL.
An action on the merits of claims 3-5, 7-22, and 28 is set forth herein. Claims 1, 2, 23-27, and 29-31 are withdrawn from consideration as being directed to a non-elected invention.
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.
Claims 3-5, 7-22, and 28 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural correlation/law of nature and an abstract idea without significantly more. This judicial exception is not integrated into a practical application and the claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons set forth below.
35 U.S.C. § 101 requires that to be patent-eligible, an invention (1) must be directed to one of the four statutory categories, and (2) must not be wholly directed to subject matter encompassing a judicially recognized exception. M.P.E.P. § 2106. Regarding judicial exceptions, “[p]henomena of nature, though just discovered, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work.” Gottschalk v. Benson, 409 U.S. 63, 67 (1972); see also M.P.E.P. § 2106. The unpatentability of abstract ideas was confirmed by the U.S. Supreme court in Bilski v. Kappos, 561 U.S. 593, 601 (June 28, 2010) and Alice Corp. Pty. Ltd. v. CLS Bank Int’l, 134 S. Ct. 2347, 2354 (2014). See also Myriad v Ambry, CAFC 2014-1361, -1366, December 17, 2014. The unpatentability of laws of nature was confirmed by the U.S. Supreme Court in Mayo Collaborative Services v. Prometheus Laboratories, Inc., 566 U.S. 66, 71 (2012). “[L]aws of nature, natural phenomena, and abstract ideas” are not patentable. Dia-mond v. Diehr, 450 U. S. 175, 185 (1981); see also Bilski v. Kappos, 561 U. S. at 601 (2010).
Claims Analysis:
As set forth in MPEP 2106, the claims have been analyzed to determine whether they are directed to one of the four statutory categories (STEP 1).
The instant claims are directed to methods and therefore are directed to one of the four statutory categories of invention.
The claims are then analyzed to determine if they recite a judicial exception (JE) (STEP 2A, prong 1) [Mayo Collaborative Services v. Prometheus Labs., Inc., 132 S. Ct. 1289, 1293 (2012), Alice Corp. Pry. Ltd. v. CLS Bank Int'l, 134 S. Ct. 2347 (2014)].
The claimed invention recites a method of determining whether a patient would be a suitable responder to the use of a CD123 X CD3 bispecific molecule to treat a hematological malignancy by evaluating the expression of target genes in one or more target gene signatures, as well as treating the patient with a treatment dosage of the CD123XCD3 bispecific molecule if the patient is determined to be suitable for treatment. However, this recitation is a natural correlation between expression levels of genes and treatment efficacy of a CD123XCD3 bispecific molecule. With regard to the natural correlation, as in Mayo, the relationship is itself a natural process that exists apart from any human action. The claimed invention also recites a number of abstract steps, including: “determining whether a patient would be a suitable responder”, “evaluating expression of one or more target genes”, “identifying said patient as a suitable responder”, “evaluating expression of one or more reference genes”, “evaluating” expression relative to a baseline signature, “comparing expression levels”, “assigning relative expression value”, and “determining” a target gene signature score which read on making mental determinations and comparisons. These are deemed to be abstract ideas because they can occur entirely within the mind. The claims additionally recite steps such as “normalizing” measured raw RNA levels, “averaging the gene expression level”, “log transforming each normalized RNA value”, “multiplying” by a corresponding weight factor, “adding” the weighted RNA values, and “scoring wights and optionally adjustment factors”. These steps are also directed to abstract ideas because they are directed to mathematical formulas and relationships. It is therefore determined that the claims are directed to judicial exceptions.
The claims are then analyzed to determine whether they recite an element or step that integrates the JE into a practical application (STEP 2A, prong 2) [Vanda Pharmaceuticals Inc., v. West-Ward Pharmaceuticals, 887 F.3d 1117 (Fed. Cir. 2018)].
The claims recite steps of “evaluating” gene expression levels. Although this broadly encompasses abstract mental activity, such as reading a report that lists expression levels, even if the claim required performing gene expression assays in a laboratory, both situations do not integrate the JE into a practical application because it is a mere data gathering step to use the correlation and does not add a meaningful limitation to the method. Although claim 9 recites “a method of treating”, the treatment itself is conditional as evidenced by the use of the term “if”.
In the absence of steps or elements that integrate the JE into a practical application, the additional elements/steps are considered to determine whether they add significantly more to the JE either individually or as an ordered combination, to “’transform the nature of the claim’ into a patent eligible application” [Mayo Collaborative Services v. Prometheus Labs., Inc., 132 S. Ct. 1289, 1293 (2012), Alice Corp. Pry. Ltd. v. CLS Bank Int'l, 134 S. Ct. 2347 (2014)] (STEP 2B).
In the instant situation, any step of detecting expression levels, encompassed by the term “evaluating”, is generally recited and does not provide any particular reagents that might be considered elements that transform the nature of the claims into a patent eligible application because no specific elements/steps are recited. Not only is the step of evaluating gene expression a mere data gathering step, but the general recitation of detection of known nucleic acids is well understood, routine, and conventional activity (See MPEP 2106.05(d)(II)). Applicant is reminded that in Mayo, the Court found that “[i]f a law of nature is not patentable, then neither is a process reciting a law of nature, unless that process has additional features that provide practical assurance that the process is more than a drafting effort designed to monopolize the law of nature itself." Further "conventional or obvious" "[pre]solution activity" is normally not sufficient to transform an unpatentable law of nature into a patent-eligible application of such a law”. Flook, 437 U. S., at 590; see also Bilski, 561 U. S., at ___ (slip op., at 14) (“[T]he prohibition against patenting abstract ideas ‘cannot be circumvented by’ . . . adding ‘insignificant post-solution activity’” (quoting Diehr, supra, at 191–192)). The Court also summarized their holding by stating “[t]o put the matter more succinctly, the claims inform a relevant audience about certain laws of nature; any additional steps consist of well understood, routine, conventional activity already engaged in by the scientific community; and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately.” Therefore these limitations/steps do not “‘transform the nature of the claim’ into a patent-eligible application.’” Alice, 134 S. Ct. at 2355 (quoting Mayo, 132 S. Ct. at 1297).
When viewed as an ordered combination, the claimed limitations are directed to nothing more than the determination that a natural correlation/phenomena exists. Any additional element consists of using well understood, routine and conventional activity, and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately.
Accordingly, it is determined that the instant claims are not directed to patent eligible subject matter.
Claim Rejections - 35 USC § 112
112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Claims 3-5, 7-12, 14-22, and 28 are rejected under 35 U.S.C. 112(a) 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, at the time the application was filed, had possession of the claimed invention.
The claims are broadly drawn to methods of determining whether a patient would be a suitable responder to the use of a CD123 X CD3 bispecific molecule to treat a hematological malignancy by evaluating the expression of structurally undefined target genes in one or more structurally undefined target gene signatures, including, for example, an “IFN Gamma Signaling Signature”.
Relevant to the lack of particular structural limitations in the rejected claims, MPEP 2163 states:
The claimed invention as a whole may not be adequately described if the claims require an essential or critical feature which is not adequately described in the specification and which is not conventional in the art or known to one of ordinary skill in the art.
Additionally, at 2163IIA3(a), the MPEP states:
“…describing a composition by its function alone typically will not suffice to sufficiently describe the composition. See Eli Lilly, 119 F.3 at 1568, 43 USPQ2d at 1406 (Holding that description of a gene’s function will not enable claims to the gene “because it is only an indication of what the gene does, rather than what it is.”); see also Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen Inc. v. Chugai Pharm. Co., 927 F.2d 1200, 18 USPQ2d 1016 (Fed. Cir. 1991)). An adequate written description of a chemical invention also requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed. See, e.g., Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004) (The patent at issue claimed a method of selectively inhibiting PGHS-2 activity by administering a non-steroidal compound that selectively inhibits activity of the PGHS-2 gene product, however the patent did not disclose any compounds that can be used in the claimed methods. While there was a description of assays for screening compounds to identify those that inhibit the expression or activity of the PGHS-2 gene product, there was no disclosure of which peptides, polynucleotides, and small organic molecules selectively inhibit PGHS-2. The court held that “[w]ithout such disclosure, the claimed methods cannot be said to have been described.”).
The claims require determining whether a patient would be a responder to to the use of a CD123 X CD3 bispecific molecule by evaluating the expression of structurally undefined gene signatures. In the case of the instant claims, the functionality of identifying genes that would mee the functional requirements of the claims is a critical feature of the claimed methods.
The specification teaches measuring gene expression signatures from RNA isolated from bone marrow samples, using the nCounter system, allowing for multiplexed mRNA quantification of low abundance transcripts, in patients with AML receiving treatment with flotetuzumab (DART-A). The specification teaches that the method compared the gene expression profiles of 750 genes using the NanoString PanCancer IO360TM assay. The specification teaches 4 genes and their weight factors (table 6, page 105): STAT1, CXCL9, CXCL10, and CXCL11 directed to IFN Gamma Signaling, for example. The specification teaches that responders to flotetuzumab showed significantly higher scores for these 4 genes compared to non-responders (specification page 109). However, the specification does not provide a predictable structure/function correlation between these genes, the gene signature they belong to, and response to flotetuzumab in AML patients. While the specification exemplifies that a gene signature directed to these four genes can be used to predict response to flotetuzumab, these four genes are not representative of the broad scope of possible genes that are within the claimed genus. The claims encompass a genus of structurally undefined genes which must identify a patient as a suitable responder to a CD123 X CD3 bispecific molecule, however, other than the four genes discussed above, the specification does not provide guidance to the skilled artisan to distinguish which genes belong to the genus with the required functionality from those that do not.
While the skilled artisan may be capable of making performing the nCounter assay, possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features. See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895.
For claims drawn to a genus, the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species. A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that “only describe[d] one type of structurally similar antibodies” that “are not representative of the full variety or scope of the genus.”). The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure “indicates that the patentee has invented species sufficient to constitute the gen[us].” See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615. Further, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 held that:
To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention.” Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (“ [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed.”). Thus, an applicant complies with the written description requirement “by describing the invention, with all its claimed limitations, not that which makes it obvious,” and by using “such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention.” Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.
Thus considering the breadth of the genes required by the claimed methods, their specific required functionalities, and the teachings of the instant specification, it is the conclusion that the specification does not provide an adequate written description of the broadly claimed subject matter.
112(b)
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.
Claims 4, 8, 11, 12, 17, 18, and 20-22 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
The phrase “characteristically associated” in claim 4 has not been defined by the specification and is unclear. Neither the claims nor the specification define what is required for a gene to be considered “characteristic” of any phenotype, or the degree to which an gene is or is not involved in any particular pathway to be considered “associated” with a hematological malignancy vs not. Accordingly, the metes and bounds of the claim are unclear.
The phrase “at least about 0.4” in claim 8 is unclear. The recitation of “at least” is used to indicate a minimum number or value, however this is controverted by the use of the term “about” which allows for less than any particular minimum. For example, the value of 0.3 is less than the minimum of 0.4, however it is not clear if 0.3 is encompassed by the claim or not. The same analysis holds for the phrase “at least about” in claim 20.
The recitation of “said one or more reference genes” in claim 11 lacks sufficient antecedent basis because neither claim 11 nor claim 3 (the claim from which it depends) recite any reference genes.
The phrase “internal reference genes” in claim 12, step b is unclear because it cannot be determined whether this refers to the reference housekeeping genes in step a, or if it is a different set of reference genes. If the latter is the case, it is not clear what is required to determine wither a reference gene is an “internal” reference gene or not.
Claim 17 is indefinite for being incomplete because it references elements in tables. As set forth in the MPEP 2173.05(s):
Reference to Figures or Tables
Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table “is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.” Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted).
Additionally, the relationship between the adjustment factors listed in the tables and the gene signature score are unclear because the claim does not provide any clarity as to how the adjustment factors are used to calculate the gene signature score.
The recitation of “the IFN Gamma Signaling Signature”, “the Tumor Inflammation Signature”, etc in claims 18, 20, and 21 lack sufficient antecedent basis because neither this claim nor the claims from which it depends set forth any “IFN Gamma Signaling Signature”, etc. Additionally, the names assigned to these signatures do not clear set forth which genes are contained within the signature. These do not appear to be art accepted terms and as such, the metes and bounds of the genes encompassed by the signatures are unclear.
Claim 22 requires a target gene expression signature that is “characteristic of an immune enriched and IFN gamma dominant tumor microenvironment”, however neither the claim nor the specification provide any definition as to what genes are encompassed by this recitation”. It is not clear how to to determine if a gene is considered “characteristic” vs not, of any particular phenotype, let alone the metes and bounds of “an immune enriched and IFN gamma dominant tumor microenvironment”.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 3-5, 7-12, 14-22, and 28 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17, 20-22, and 24 of copending Application No. 18/001,025 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘025 applicant anticipate the instantly pending claims. The claims of the instant application are directed to methods of determining whether a patient would be a suitable responder to the use of a CD123 X CD3 bispecific molecule to treat a hematologic malignancy by evaluating the expression of a target gene signature. The instant claims broadly encompass any gene signature. The claims of the ‘025 application are also directed to to methods of determining whether a patient would be a suitable responder to the use of a CD123 X CD3 bispecific molecule to treat a hematologic malignancy by evaluating the expression of a target gene signature, and recite particular genes in the target gene signature.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Bonvini (Bonvini et al; WO2017/214092; cited in the IDS filed 2/8/2022) teaches administration of flotetuzumab (DART-A; CD123 X CD3 bispecific molecule) to patients with AML. However Bonvini does not teach evaluating the gene expression of any target genes in a cellular sample from a patient prior to treatment, or comparing the gene expression to the gene expression in (i) an individual or a population of patients suffering from AML, (ii) to an individual or population of individuals who did not response to flotetuzumab, or (iii) an individual or population who successfully responded to flotetuzumab, or identifying the patient as a responder based on the gene expression of a target gene or genes.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to examiner Jehanne Sitton whose telephone number is (571) 272-0752. The examiner is a hoteling examiner and can normally be reached Mondays-Fridays from 8:00 AM to 2:00 PM Eastern Time Zone.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Winston Shen, can be reached on (571) 272-3157. The fax phone number for organization where this application or proceeding is assigned is (571) 273-8300.
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/JEHANNE S SITTON/Primary Examiner, Art Unit 1682