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
Applicant’s election without traverse of Group I, species NPM1 mutation, hypomethylating agent is the only therapeutic agent, 5-azacytidine as the hypomethylating agent, and AML as the cancer in the reply filed on 2/27/2026 is acknowledged.
After search, decitabine is rejoined to 5-azacytidine. Claim 80, decitabine, is examined with the elected invention. Additionally, MDS and claim 90 are rejoined.
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 86 and 87 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 recitation in the claims of “National Comprehensive Cancer Network 2011 guidelines” is an improper incorporation by reference of essential subject matter. The subject matter is considered essential because it is necessary to understand the metes and bounds of the claims.
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 86 and 87 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 86 and 87 are indefinite over the recitation “as defined according to the National Comprehensive Cancer Network 2011 guidelines” because the specification does not define the criteria set forth in the guidelines and there is no evidence of record as to the public availability of these guidelines. Therefore one skilled in the art would not be appraised of the metes and bounds of the guidelines.
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.
Claim 13 is rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea and a natural phenomenon without significantly more. The claim(s) recite(s) identifying the human subject as being likely to be responsive to the treatment.” This is a mental process abstract idea judicial exception, and it also sets forth the naturally occurring relationship between mutation and response to treatment, which is a law of nature judicial exception.
The instant specification teaches at ¶0054 that detecting the presence of a mutation encompasses determining whether a mutation is present or absent.
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Therefore, in claim 13, the treatment step is conditional, only being required “if” one or more mutation is present. The only required step in the claim is detecting the presence or one or more gene mutations in a sample from the patient.
This judicial exception is not integrated into a practical application because required step in addition to the judicial exception is a data gathering step and does not use or apply the judicial exception in any way. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the only step in addition to the judicial exception is a data gathering step that instructs the practitioner to detect the presence (or absence) of the one or more mutation, and is sufficiently broad so as to encompass using any known technique. The Examiner takes Official notice that molecular biology techniques for detecting mutations were well known before the effective filing date.
Amending the claim to recite that the mutation is present in the sample, and the treatment definitively occurs will overcome this rejection.
Claim Rejections - 35 USC § 112
Claim 13 is 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 for identifying a patient who is 55 or older, who has AML in first remission after intensive chemotherapy who has an NPM1 mutation as having an increased likelihood for responding to hypomethylating treatment as a singular treatment for maintenance, and treating the patient, does not reasonably provide enablement for predicting response to hypomethylating treatment based on NPM1 mutation in any cancer patient or any AML patient. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
It is further noted that insofar as Wu anticipates the instantly rejected claim, the embodiment taught by Wu is also enabled by the prior art.
The claims have been considered for the elected NPM1 gene.
The claims are sufficiently broad so as to encompass identifying any patient with any type of cancer or abnormal cell proliferation disorder s being likely to be responsive to treatment with a hypomethylating agent.
The state of the prior art at the time of the invention included Prata et al. which teaches “NPM1 mutation is not associated with prolonged complete remission” in AML patients treated with hypomethylating agents. The patients in the study were treated with hypomethylating agents because they were unfit for intensive chemotherapy. In the population studied there was no relationship between NPM1 mutation status and response to azacitidine or decitabine.
Lachoweiz taught that “The favorable prognostic impact of a NPM1 mutation is context
dependent and is particularly influenced by the presence of FLT3-ITD co-mutations.” Lachoweiz reiterates that “In NPM1+ patients considered unfit for intensive induction treated with a frontline HMA, responses remain poor (overall response rate, 45.5%; CR, 23.5%; median OS,
10 months), similar to those seen in a matched WT NPM1 cohort (p. 1312).”
Further, Dohner teaches that there was no statistically significant difference within hypomethylating treatment arm for patients with NPM1 lesions compared with patients with wildtype genes (p. 2551).
Wu teaches that NPM1 mutation ALONE was not sufficient to predict response to a hypomethylating agent, it was only when NPM1 was mutated and DNMT3A was wild type that an association between status and response was present. This is consistent with the teachings of Lachoweiz who teaches that the prognostic impact of NPM1 mutation is context dependent.
Taken together, these references exemplify that it is highly unpredictable whether the mutational status of NPM1 can identify patients having any type of cancer or proliferative disorder will respond to hypomethylating drugs, and further whether this prediction can be made for any type (i.e. front line versus maintenance) of treatment regimen even for AML. In fact, the prior art clearly teaches that such predictions cannot be made for front line, first treatment with hypomethylation agents.
In the context of the prior art and the high level of unpredictability, the specification teaches correlative analysis of gene mutations in patients from the QUAZAR study, which was a trial of azacitidine administered as maintenance therapy in patients 55 or older, with intermediate or poor risk, with AML who were in first remission after intensive chemotherapy, see specification ¶296. Figure 4A shows that mutation in NPM1 predicts favorable response to the maintenance therapy. Additional figures support this finding.
The specification does not provide any guidance as to predicting outcome to front line first treatment with hypomethylating agents or for predicting response in other cancers or other abnormal cell proliferation disorders.
Discovering additional associations, where NPM1 alone or in combination with other mutational status is predictive of response to hypomethylating treatment would require an extremely high level of experimentation in a technology area where a high level of unpredictability has been demonstrated. Such experimentation could include prospective or retrospective analysis of patient data searching for a signal, an inventive effort, as evidenced by the instant specification. There is no a priori way to predict what treatment/NPM1 mutation signals will be observed for development into a predictive method.
Thus, having carefully considered this, it is concluded that the specification was not enabling to make and use the claimed invention commensurate in scope with the instant claims.
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.
Claim(s) 1-3, 9, 10, 11, 23, 78, 80-85 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lachowiez et al. (Blood Adv (2020) 4 (7): 1311–1320; published online 6 April 2020).
The reference teaches treating a patient who has acute myeloid leukemia (AML), a cancer comprising administering to the subject a therapeutically effective amount of the hypomethylating agent azacitidine wherein the cancer is characterized by the presence of a neucleophosmin (NPM1) mutation. All patients, regardless of treatment had NPM1 mutation identified, see Figure 1.
Regarding claim 9, the reference teaches treating a patient with a RAS mutation, See Figure 1, panel A and Panel B.
Regarding claims 10 and 11, the reference teaches treatment outcome of patients treated with HMA include patients tested negative for minimal residual disease. See Table 3.
Regarding claims 23, 78, and 80, some patients were treated with HMA monotherapy (either Decitabine or Azacitidine (i.e. 5-azacytidine), p. 1313, 1st column).
Regarding claims 81, 82, and 83, the reference teaches that the patients have AML, throughout.
Regarding claim 84, the reference teaches treating patients with secondary AML (Table 1).
Regarding claim 85, the reference teaches treating “treated secondary AML” with HMA in 8 patients, Table 1. These patients have “relapsed or refectory AML.”
Claim(s) 1, 3, 9-11, 23, 78-79, 81-84, 86-87 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wei et al. (blood (2019) 134 (Supplement_2) : LBA-3.).
Wei teaches a method in which patients 55 or older with de novo AML or secondary AML, with intermediate- or poor-risk cytogenetics who had achieved first complete remission (CR) or CR with incomplete count recovery after induction chemotherapy were given the hypomethylating agent oral azacitidine, referred to therein as CC-486, as a monotherapy, See PDF p. 3.
The reference teaches that the results reported are from the clinical trial NCT01757535, but the reference is silent as to whether or not any patient treated had NPM1 mutation. The instant specification evidences that it was INHERENT to patients in the trial that they had NPM1 mutation, and thus, for at least some patients in the trial, the cancer was characterized by the presence of an NPM1 mutation. See instant specification, Example 1, which teaches in ¶0296 that the patients studied were patients from this trial.
Claim 1 does not require assaying for or identifying the presence of the mutation, merely that the cancer is “characterized by” the mutation, which is interpreted to mean that the cancer has the mutation. Therefore, inherently, the method taught by Wei anticipates claims 1 and 3.
Regarding claim 9, the NPM1 mutated patients included patients with RAS mutation, as evidenced by the instant disclosure, See at least Figure 20B, sheet 53.
Regarding claims 10 and 11, the NPM1 mutated patients included patients with no MRD, See Figure 6C.
Regarding claim 23, the reference only teaches delivering CC-486 as monotherapy.
Regarding claims 78-79, CC-486 comprises 5-azacytidine, and the composition is non-enteric-coated, as evidenced at least by the instant disclosure, ¶263. These are inherent features of the drug given in the disclosed trial.
With regard to claim 81-83, the disclosed trial inherently treated NMP1 mutation patients with the hematological cancer AML (see Methods).
With regard to claim 84, the AML is secondary to prior MDS or CMML. The reference teaches that some patients had “secondary” AML, and the trial report evidences that this meant secondary to MDS or CMML (pdf page 4, Detailed Description). Since 137/469 patients in the trial had NPM1 mutation (Figure 4B), the preponderance of evidence supports that at least one treated patient with secondary AML was treated with CC-486.
With regard to claim 86 and 87, these claims are indefinite, however, the reference clearly teaches that the patients had intermediate and poor risk cytogenetics (Methods), and the instant specification evidences that for the trial this was determined by the 2012 NCCN guidelines ¶0303.
Claim(s) 1-3, 9, 13, 23, 80, 81-87, and 90 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wu et al. (British Journal of Haematology, 2020, 189, 982–992).
Wu teaches a method that includes detecting the presence of NPM1 mutation in a sample obtained from a human subject. Wu reports that 12 patients harbored the NPM1 mutation; Wu does not mention obtaining a sample, but the reference footnoted indicates that high throughput sequencing was completed (see Reference 3, Wu).
Wu further teaches identifying human subjects as likely to be responsive to the hypomethylating agent decitabine if they are NPM1 positive and DNMT3A wild type stating that these patients “have a good response to treatment and prolonged survival on decitabine (p. 982, 2nd column).”
Wu further teaches treating these patients with decitabine.
Thus, Wu anticipates claim 1-3, and 13.
Wu further anticipated claim 13 because Wu teaches that a total of 194 patients were considered, and only 12 of them had NPM1 mutation. The claimed method requires detecting the presence (or absence, see ¶0054 of the specification) of an NPM1 mutation (consonant with the election. In 182 patients tested, the “absence” of a mutation was identified. Following this steps (a)(ii) and (b) of the claim are not required to be practiced since they are practiced “if one or more gene mutations (in NPM1) are detected. Therefore, this additional embodiment of claim 13 is also anticipated by Wu.
Regarding claim 9, Table 1 teaches a patient who has NPM1 mutation and NRAS mutation, since Wu is reporting the NRAS mutation, lack of reporting RAS mutation in other NPM1 positive patients is evidence that these patients DID NOT have cancers with RAS mutation.
Regarding claim 23, the drug is given as monotherapy (see Col. 1, p. 982).
Regarding claim 80, the hypomethylating agent is decitabine.
Regarding claims 81-87 and 90, the claims further define “the cancer” of claim 1 but does not require that the patient have cancer. The patients taught by Wu have MDS, “a disorder related to abnormal cell proliferation.”
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Juliet Switzer whose telephone number is (571)272-0753. The examiner can normally be reached Monday to Thursday, 8:00 AM-3:30 PM.
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Juliet Switzer
Primary Examiner
Art Unit 1682
/JULIET C SWITZER/Primary Examiner, Art Unit 1682
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