DETAILED ACTION
Status of Application, Amendments and/or Claims
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The claim listing filed on 4/1/26 has been entered; no amendments are indicated. Claims 1-8 are pending.
The election of “lymphoblasts/lymphocytes” as the species of sample in the reply filed on 4/1/26 is acknowledged. Claims 5 and 6 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claims 1-4, 7 and 8 are under consideration, as they read upon the elected species.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Specification
The disclosure is objected to for the following informalities:
---The title is not descriptive because it is directed generally to any method for estimating the toxicity level of radiation therapy in a patient, but the claimed method is limited to such a method based on steps of determining a radiosensitivity factor based on biochemical analysis and a treatment factor based on dosimetric data. A new title is required that is clearly indicative of the invention to which the claims are directed. In view of the rejection of the claims under 35 U.S.C. 112(a), the following title is suggested: “Method for Estimating the Toxicity Level of Radiation Therapy on a Patient Combining Determining the Amount of pATM Protein and Analyzing Dosimetric Data”.
Claim Objections
Claims 1-4, 7 and 8 are objected to because of the following informalities:
In claim 1, the following recitations are redundant and one should be removed: “determine a first radiosensitivity factor by a biochemical analysis” (line 4) and
“wherein the first radiosensitivity factor is determined by a method for biochemical analysis” (lines 4-5).
In claim 4, “phosphorylated ATM protein pATM” should be “phosphorylated ATM protein (pATM)”.
In claim 4, “of the sample” should be “in the sample”.
In claim 7, “on lymphoblasts” should be “in lymphoblasts”.
The remaining claim(s) are objected to for depending from an objected claim.
Appropriate correction is required.
Claim Rejections - 35 USC § 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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-4, 7 and 8 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 pre-AIA the applicant regards as the invention.
In claim 1, the preamble states that the method is for “estimating a toxicity level”, but the concluding wherein clause instead has that “the level of toxicity is determined”. It is unclear if the scope of “estimating” and “determining” is the same, and thus the claim is indefinite because the goal (estimating) does not match the conclusion (determined).
Claim 2 recites the limitation “the radiosensitivity factor representative of the ability of a patient to tolerate further radiation in the context of radiation therapy” in lines 2-3. There is insufficient antecedent basis for this limitation in the claim. Specifically, parent claim 1 refers to “a first radiosensitivity factor”, but not “a radiosensitivity factor representative of…”, and as such there is no antecedent basis for the limitation.
Claim 2 recites the limitation “the sample collected with or without application of radiation after collection” in lines 2-3. There is insufficient antecedent basis for this limitation in the claim. Specifically, parent claim 1 refers to “a cell sample having been obtained from cells collected from a patient”, but not “a sample collected with or without application of radiation after collection”, and as such there is no antecedent basis for the limitation in claim 2.
Claim 2 is also indefinite because it says that the “the radiosensitivity factor” is “determined based on two protocols”, which are “an in vitro radiosensitivity analysis” and “a dosimetric analysis”, but the dosimetric analysis of claim 1 is for a treatment factor, not the radiosensitivity factor, and claim 2 in fact states that the dosimetric analysis is to establish a treatment factor.
Claim 3 recites the limitation “the factor” in line 1. There is insufficient antecedent basis for this limitation in the claim. Specifically, parent claim 1 refers to a “first radiosensitivity factor” and a “second treatment factor”, and it is unclear which is being referred to by “the factor” in claim 3.
In claim 7, the term “lymphoblasts/lymphocytes” is indefinite because it is unclear if it refers to “lymphoblasts and lymphocytes” or “lymphoblasts or lymphocytes”.
Claim 8 recites the limitations “the pATM test” and “the blood lymphocytes” in line 3, and “the prediction using dosimetric models” in line 4. There is insufficient antecedent basis for these limitations in the claim. Specifically, parent claim 1 does not refer to a pATM test, blood lymphocytes or a prediction using dosimetric models, and thus does not provide antecedent basis for these limitations in claim 8.
Claim 8 is indefinite because it further limits the determination of the toxicity level to one that is “determined by adjusting bivariate logistic regression models” including the results of pATM test and dosimetric model prediction, but fails to indicate how this determination relates to the two steps of the parent claim which are required to be performed and combined to determine the level of toxicity.
The remaining claim(s) included in the rejection are dependent claims that depend from one of the claims rejected above, and encompass the same indefinite subject matter.
Claim Rejections - 35 USC § 112(a), written description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.-The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-3, 7 and 8 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.
Per MPEP 2163, 35 U.S.C. 112(a) requires, “separate and distinct from the enablement requirement”, that the “specification shall contain a written description of the invention…” (Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1355 (Fed. Cir. 2010)). In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112(a), it is necessary to understand what Applicants are claiming and what Applicants have possession of.
The instant claims are directed to a method intended to estimate a patient’s toxicity level from radiation therapy. The method comprises two steps: (1) characterizing radiosensitivity to ionizing radiation of a cell sample collected from the patient under examination in the basal state, to determine a first radiosensitivity factor by a biochemical analysis, and (2) analyzing dosimetric data using data originating from treatment planning to determine a second treatment factor; wherein the level of toxicity is determined by a combination of the first and second factors. The claims are genus claims because they encompass analyzing any factor in a sample from the patient, which encompasses measuring any protein, antibody, nucleic acid, carbohydrate, lipid, small organic molecule or inorganic molecule in a sample. The specification provides an example of the claimed method wherein the radiosensitivity factor that is measured is phosphorylated ATM protein (pATM), a kinase (¶ 26, 27), including a working example (¶ 85). No other examples of factors that can be measured are provided. The specification further asserts that a “genetic factor” or “genomic analysis” (¶ 13) can be determined instead of the pATM level. The specification further states that DNA can be sequenced to “qualify markers or a combination of markers, especially of DNA polymorphisms” (¶ 60). As such, the “genetic factor” is directed to a genus of DNA markers. However, the specification fails to provide any specific examples of such markers or other genetic factors, and there are no working examples supporting the use of such. Furthermore, there is no description of what genetic factors can be combined with dosimetric data to determine a toxicity level.
Written description for a genus may also be satisfied through sufficient description of a relevant number of species. This is dependent on whether one of skill in the art would recognize necessary common attributes or features possessed by the members of the genus. Generally, in an unpredictable art, adequate description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), clearly states “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed” (pg 1117). The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed” (pg 1116).
Therefore, only a method of claim 1, wherein the radiosensitivity factor is determined by determining an amount of phosphorylated ATM protein (pATM) in the sample in the basal state, but the not the full breadth of the claims meet the written description provision of 35 U.S.C. §112(a). Applicants are reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (pg 1115).
Note on Prior Art Rejection(s)
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 1-2, 4, 7 and 8 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Deneuve et al, 2019, International Journal of Radiation Oncology, Vol. 105, Issue 1, Supplement S221, Abstract 1229, 1 page as printed. The earliest date to which the instant application claims priority is 3/5/21.
Claim 1 encompasses a method for estimating a toxicity level of radiation therapy on a patient, comprising two steps: (1) characterizing radiosensitivity to ionizing radiation of a cell sample collected from the patient under examination in the basal state, to determine a first radiosensitivity factor by a biochemical analysis, and (2) analyzing dosimetric data using data originating from treatment planning to determine a second treatment factor; wherein the level of toxicity is determined by a combination of the first and second factors.
The Deneuve publication is titled, “Approach Combining Dosimetry and Biology to Predict Severe Toxicity of Radiotherapy for Head and Neck Squamous Cell Carcinomas”. Deneuve teaches that “the role of the nucleoshuttling of the phosphorylated form of the ATM protein (pATM) in response to radiation, and the discrimination power of this molecular endpoint in predicting individual radiosensitivity” (see “Purpose/Objective”). Deneuve teaches an assay of lymphocytes for “quantification of the pATM by ELISA” to predict patients’ “risk of acute toxicity” (see “Purpose/Objective”). As the sample is taken and measured for prediction of risk, it meets the limitation of the sample being in the basal state. Deneuve further teaches “a model combining dosimetry and the lymphocyte assay” (see “Purpose/Objective”) to yield the toxicity prediction as indicated in the title. As such, Deneuve teaches a method that meets each of the limitation of claim 1.
Claim 2 encompasses a method of claim 1 wherein the determination is based on the results of at least two protocols, including an in vitro radiosensitivity analysis carried out on a biological sample collected without application of radiation, which is met by the quantification of pATM in lymphocytes as taught by Deneuve (see above), and a dosimetric analysis of the treatment planning system (TPS) established to prepare a radiation treatment plan for radiation therapy, which is met by the further teaching of Deneuve that “[t]wo previously developed dosimetric models were considered” (see “Materials/Methods”). As such, the teachings of Deneuve also meet the limitations of claim 2.
Claim 4 encompasses a method of claim 1 wherein the radiosensitivity factor is determined by determining an amount of pATM protein in the sample in the basal state. The teachings of Deneuve that anticipate parent claim 1 are directed to measuring the amount of pATM in the sample in the basal state. As such, the teachings of Deneuve anticipate claim 4 for the same reasons as for claim 1.
Claim 7 encompasses a method of claim 1 wherein the radiosensitivity factor is determined in lymphoblasts/lymphocytes originating from a blood sample of the patient. The teachings of Deneuve that anticipate parent claim 1 are directed to measuring the amount of pATM in the lymphocytes of the patients. As such, the teachings of Deneuve anticipate claim 7 for the same reasons as for claim 1.
Claim 8 encompasses a method of claim 1 wherein the toxicity level is determined by adjust bivariate logistic regression models, which comprises (a) the result of the pATM test on the blood lymphocytes; and (b) the prediction using dosimetric models based on treatment planning dosimetric data for toxicities of grade ≥ 2 or 3. This claim is indefinite for several reasons as set forth above in the section, “Claim Rejections 35 USC § 112(b)”, including because it is not clear how this further limitation regarding determining the toxicity level relates to the two steps that are required to be carried out in the parent claim to determine the toxicity level. However, Deneuve further teaches that “[t]he combined model was defined as a logistic model including prediction from the previously published dosimetric model … and classification by the pATM assay” (see “Materials/Methods”), which was measured in lymphocytes. The two variables (dosimetry and pATM) render the model bivariate. Deneuve further teaches that the model combining dosimetry and the lymphocyte assay relied on dosimetric data from patients with toxicities of “grade≥3” (see “Materials/Methods”). Deneuve further teaches that the combined model yielded ORs (odds ratios) (see “Results”), which is an output of logistic regression model that estimates the probability of occurrence. As such, the teachings of Deneuve also include the further limitations presented in claim 8.
Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZACHARY C HOWARD whose telephone number is (571)272-2877. The examiner can normally be reached on Monday to Friday from 9 AM to 5 PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Vanessa Ford, can be reached at telephone number (571) 272-0857. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ZACHARY C HOWARD/Primary Examiner, Art Unit 1674
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