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 .
Response to Amendment
The amendment filed December 10th, 2025 is acknowledged. Regarding the Office Action mailed September 22nd, 2025:
The objections to the claims are withdrawn in view of the amendments.
The rejections of claims 1, 3, 4, 7, 11, 13, 14, and 25 set forth under 35 U.S.C. 112(b) are withdrawn in view of the amendments and the cancellation of claims 3 and 13. The rejections of claims 6, 8-10, 16, and 18-20 are maintained and set forth below.
The rejection set forth under 35 U.S.C. 112(a) is withdrawn in view of the amendments.
The rejection set forth under 35 U.S.C. 103 is withdrawn in view of the amendments.
Maintained or modified rejections are set forth below.
New grounds of rejection are set forth below, as necessitated by the amendments and further considerations. Responses to arguments, if necessary, follow their respective rejection sections.
Claim Summary
Claims 1-2, 4-7, 11-12, 14-18, and 24-25 have been amended. Claims 3, 13, and 21-23 have been canceled. Claims 26 and 27 have been added. Claims 1-2, 4-12, 14-20, and 24-27 are pending. Claims 1-2, 4-12, 14-20, and 24-27 are under examination and discussed in this Office action.
Claim Interpretation – Modified – Necessitated by Amendment
The claims are directed towards methods related to diffuse glioma. Looking to the specification for a definition of diffuse glioma, the Applicant defines it as “a term used to encompass a variety of tumors of the central nervous system, which histologically appear similar to glial cells, such as astrocytomas, oligodendrogliomas and oligoastrocytomas, ranging from WHO grade II to grade IV tumors.” (Page 6, paragraph [0023]). The Applicant also defines glioblastoma as a grade IV astrocytoma (Page 30, paragraph [0094]). This definition is being used to interpret diffuse gliomas throughout this Office Action.
Claim 11 recites the limitation “assessing therapy responsiveness in the subject based on the mutational status and the methylation level of the genes”. Looking to the specification for a definition of this recitation, the Applicant defines assessing responsiveness to a therapeutic agent as the determination of the likelihood of a subject for responding or not responding to the therapeutic agent (Pages 19-20, paragraph [0052]). This definition is being used to interpret this recitation throughout this Office Action.
Claim Rejections - 35 USC § 112(b) – New and Modified – Necessitated by Amendment
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 1-2, 4-12, 14-20, and 24-27 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.
New
Claims 1, 11, 24, and 25 recite the limitation "in at least a portion of the exon 1 and intron 1". There is insufficient antecedent basis for this limitation in the claim. There is no previous introduction of “exon 1 and intron 1” earlier in any of the cited claims. Claims 2, 4-10, 12, 14-20, and 26-27 are also rejected here for their dependence on claims 1, 11, 24, and 25 and suffering from the same antecedent basis issue.
Modified
Claims 6 and 16 recite the limitation “targeted double strand breaks are generated with crRNAs, wherein each of the crRNA binds to a sequence in each of the IDH1, IDH2, and MGMT genes”. It is unclear from this recitation if every crRNA is meant to bind a sequence in each of IDH1, IDH2, and MGMT, or if there are crRNAs that are associated specifically with each gene as claimed in dependent claim 7. Generally, crRNAs are specific to the gene to which they bind, and therefore it is unclear how a number of different crRNAs which appear to be intended for specific targets will bind to a sequence in each of IDH1, IDH2, and MGMT, which presumably have completely different sequences. It should be made clear that not every crRNA will bind to a sequence in every gene claimed, and there are instead specific crRNAs associated with IDH1, IDH2, and MGMT. Claims 8-10 depend from claim 6 and therefore suffer from the same issue. The same deficiency is noted for claim 16, and its dependent claims 18-20.
Response to Arguments
Applicant's arguments filed December 10th, 2025 have been fully considered but they are not persuasive.
With regards to the amendments to claim 6 and 16 introduced in the most recent claim listing, the Applicant states that given the amendments, they claims have sufficient clarity. As noted above, these amendments have not solved the clarity issues and need to be further addressed. Therefore, the rejection is modified as necessitated by amendment.
Claim Rejections - 35 USC § 112(a) – New – Necessitated by Further Considerations
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.
Scope of Enablement
Claims 1-2, 4-12, 14-20, and 24-27 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, for issues related to scope of enablement. With regards to claims 1-2, 4-12, 14-20, and 24-27, the specification, while being enabling for a human subject, does not reasonably provide enablement for any subject as embraced by the claims. With regards to claims 11-12, 14-20, and 25-27, the specification, while being enabling for temozolomide, does not reasonably provide enablement for any chemotherapy as embraced by the claims. With regards to claims 1-2, 4-10 and 24, the specification, while being enabling for the mutation status of IDH1 or IDH2 indicating a subject has a diffuse glioma, does not reasonably provide enablement for the mutation status of IDH1 and IDH2 indicating a subject has a diffuse glioma as embraced by the claims.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.” See MPEP § 2164. These factors include, but are not limited to: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The office has analyzed the specification in direct accordance to the factors outlines in In re Wands. MPEP 2164.04 states: “[W]hile the analysis and conclusion of a lack of enablement are based on factors discussed in MPEP 2164.01(a) and the evidence as whole, it is not necessary to discuss each factor in written enablement rejection.” These factors will be analyzed, in turn, to demonstrate that one of ordinary skill in the art would have had to perform “undue experimentation” to make and/or use the invention and therefore, applicant’s claims are not enabled.
(A) With respect to the breadth of the claims: Claims 1, 11, 24, and 25 as currently drafted encompass methods for treating a subject having diffuse glioma via detecting mutation status of IDH1 and IDH2 and methylation levels in MGMT and administering a treatment to the subject. “A subject” and “the subject” does not limit the subject to a human subject to the analysis of human samples as described in the specification. Consequently, the breadth of the claims is expansive since they encompass any kind of subject. Claims 2, 4-10, 12, 14-20, and 26-27 encompass the same breadth as claims 1, 11, 24, and 25 since they do not limit the subjects to human subjects.
Claims 11 and 25 as currently drafted encompass methods for treating a subject having diffuse glioma via detecting mutation status of IDH1 and IDH2 and methylation levels in MGMT, assessing therapy responsiveness to a chemotherapy based on the mutation and methylation, and administering a treatment to the subject. “A chemotherapy” does not limit the chemotherapy to temozolomide as described in the specification. Consequently, the breadth of the claims is expansive since they encompass any kind of subject. Claims 12, 14-20, and 26-27 encompass the same breadth as claims 11 and 25 since they do not limit the chemotherapy to temozolomide.
Claims 1 and 24 as currently drafted encompass methods for treating a subject having diffuse glioma via detecting mutation status of IDH1 and IDH2 and methylation levels in MGMT, and administering a treatment to the subject when the mutation status of IDH1 and IDH2 and the methylation levels of MGMT deviate from a reference value. Both IDH1 and IDH2 deviating from a reference value does not limit mutation status deviating from a reference to either IDH1 or IDH2 as described in the specification. Consequently, the claims as currently written are not enabled for the full scope as claimed. Claims 2-10 encompass the same breadth as clam 1 since they do not limit the mutations that deviate from a reference value to either IDH1 or IDH2.
(B) The nature of the invention: The invention is in the field of methods for detection and treatment of diffuse gliomas and assessing responsiveness to treatment.
(C), (D), (E) With respect to the state of the prior art, the level of one of ordinary skill and predictability of the art: Juppner (Functional properties of the PTH/PTHrP receptor, Bone, August 1995, S39-S42) teaches that despite significant structural conservation, rat, opossum, and human PTH/PTHrP receptor homologs display distinct functional characteristics (Abstract; Pages 39S-40S). This art indicates that there is known functional differences between homologs in different organisms, and therefore inter-species extrapolation would be unpredictable.
Shaw (MGMT in TMZ-based glioma therapy: Multifaceted insights and clinical trial perspectives, Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, March 2024, 1871, 1-19) teaches that expression of MGMT is associated with responsiveness to temozolomide (Abstract). Increased expression is resistant to treatment with temozolomide, while promoter methylation leading to subsequent reduction in expression is responsive to treatment with temozolomide (Abstract). This art indicates that there is a known relationship between MGMT expression resulting from changes in methylation and responsiveness to temozolomide. There is no indication that there is an association between MGMT methylation and responsiveness to any chemotherapy, making this unpredictable.
Picca (The clinical use of IDH1 and IDH2 mutations in gliomas, HAL Open Science, January 2019, 1-12) teaches that IDH1 and IDH2 mutations are mutually exclusive. This art indicates that either IDH1 will be mutated or IDH2 will be mutated with relation to diffuse glioma, not both, making both being mutated unpredictable.
The art supports use of specific subjects, using temozolomide given methylation affecting expression of MGMT, and either IDH1 or IDH2 being mutated. However, methods comprising any subject, methods comprising any chemotherapy, and methods where both IDH1 and IDH2 are mutated are highly unpredictable.
The invention is drawn to biological molecules, and is therefore in a class of invention which the CAFC has characterized as “the unpredictable arts such as chemistry and biology.” Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001). The level of skill in the art is therefore deemed to be high.
(F), (G) With respect to the amount of direction and working examples provided by the applicant: While the Applicant has provided description of multiple types of subjects (paragraphs [0061] and [0087]), the working examples provided by the Applicant are directed to only human subjects. As noted in paragraphs [0098]-[0103] and Table 1, the samples used in the working examples are clinical samples from humans. The Applicant has not provided working examples directed towards any other type of subject.
The Applicant has provided description (paragraphs [0045], [0094], [0096], [0128]) and working examples (paragraphs [0122], [0123], [0129]) directed towards MGMT methylation being related to response to temozolomide treatment. The Applicant has not provided description or working examples directed towards any other chemotherapy.
The Applicant has provided working examples related to either IDH1 or IDH2 being mutated (see Figures 2D and 4D; paragraphs [0121] and [0125]). The Applicant has not provided description or working examples directed towards both IDH1 and IDH2 being mutated.
Overall, the Applicant’s instant disclosure provides adequate direction and working examples for human subjects, MGMT expression resulting from changes in methylation and responsiveness to temozolomide, and mutation of either IDH1 or IDH2. The Applicant’s instant disclosure has not provided adequate direction and working examples for any subject, any chemotherapy, and mutation of both IDH1 and IDH2.
(H) Undue experimentation would be required to practice the invention as claimed due to the amount of experimentation necessary because of the expansive breadth of the claims, the state of the prior art and its high predictability, and the limited amount of guidance in the form of varied working examples in the specification. A skilled artisan recognizes that a subject very broadly refers to any number of different species and thus applicability of the claimed method to a subject as embraced by the claims remains unpredictable, requiring undue experimentation. Similarly, a skilled artisan recognizes that a chemotherapy broadly refers to any chemotherapy and thus applicability of the claimed method to a chemotherapy as embraced by the claims remains unpredictable, requiring undue experimentation. Finally, a skilled artisan recognizes that mutation status of IDH1 and IDH2 is different from mutation status of IDH1 or IDH2 and thus applicability of the claimed method to mutation status of both as embraced by the claims remains unpredictable, requiring undue experimentation. For example, an artisan would need to perform the claimed methods in an expansive number of different organisms, with controls to match. Furthermore, an artisan would need to perform multiyear studies to determine response to any chemotherapy used for treatment to see if each relates in some way to MGMT methylation and expression. Finally, an artisan would need to perform studies to examine if it is possible for both IDH1 and IDH2 to be mutated, and further that this can be associated with detection of diffuse glioma. This reasonably represents undue experimentation.
MPEP §2164.01(a), 4th paragraph, provides that, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1157, 1562; 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
Genentech Inc. v. Novo Nordisk A/S, 42 USPQ2d 1001, 1005 (CA FC), states that, “[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable,” citing Brenner v. Manson, 383 U.S. 519, 536 (1966) (stating, in the context of the utility requirement, that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion”). The Genentech decision continued, “tossing out the mere germ of an idea does not constitute enabling disclosure. While every aspect of a generic claim certainly need not have been carried out by an inventor, or exemplified in the specification, reasonable detail must be provided in order to enable members of the public to understand and carry out the invention.” Id. at p. 1005.
After applying the Wands factors and analysis to claims 1-2, 4-12, 14-20, and 24-27, in view of the applicant’s entire disclosure, and considering the In re Wright, In re Fisher and Genentech decisions discussed above, it is concluded that the practice of the full scope of the invention as claimed would not be enabled by the written disclosure. Therefore, claims 1-2, 4-12, 14-20, and 24-27 are rejected under 35 U.S.C. §112(a) for failing to disclose sufficient information to enable a person of skill in the art to practice the claimed invention to it the full scope embraced by the claims.
Written Description
Claims 11-20 and 25-27 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.
In making a determination of whether the application complies with the written description requirement under 35 U.S.C. 112(a) or 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant is claiming and what Applicant has possession of. To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V, v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was “ready for patenting” such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaff v. Wells Eiees., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641,1647 (1998); Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm., 927 F. 2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991). See MPEP § 2163.
Claim 11 recites “[a] method of treating a subject having or suspected of having a diffuse glioma, the method comprising…e) assessing therapy responsiveness in the subject based on the mutational status and the methylation level of the genes; wherein, an increase in methylation levels in at least a portion of the exon 1; or a decrease in the methylation level in at least a portion of intron 1; and detection of a substitution at R132 of IDH1 or a substitution at R172 of IDH2 indicates that the subject has a diffuse glioma that is likely to respond to a chemotherapy; and f) administering to the subject indicated as likely to respond to chemotherapy a treatment comprising chemotherapy.” Claim 25 recites “[a] method of treating a diffuse glioma in a subject in need thereof, comprising…wherein an increase in methylation levels in at least a portion the exon 1; or a decrease in the methylation level in at least a portion of the intron 1; and detection of a substitution at R132 of IDH1; or a substitution at R172 of IDH2 indicates that the subject is likely to respond to chemotherapy.” The claims as written embrace methods wherein both methylation of MGMT and substitutions in IDH1 or IDH2 are indicative of a response to chemotherapy. However, substitutions of IDH1 or IDH2 being indicative of a response to chemotherapy is not further defined or described in the claims.
Regarding this issue of IDH1 or IDH2 substitutions being indicative of a response to chemotherapy, the specification does not describe or define this capability of IDH1 and IDH2 substitutions. The specification has several instances of describing mutations in IDH1 and IDH2 as providing diagnostic information for determining the presence or absence of diffuse glioma, such as at paragraphs [0046] and [0094]. However, there is no indication anywhere in the instant disclosure that, either together with MGMT methylation or alone, IDH1 or IDH2 mutations as claimed can be used to assess chemotherapy responsiveness. Based on the specification, the Applicant does not have possession of the methods of claims 11 and 25 as claimed. Claims 12-20 and 26-27 are also rejected here for their dependence on claims 11 and 25 and also lacking possession of IDH1 or IDH2 mutations being used to assess chemotherapy responsiveness.
Conclusion
All claims are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Allison E Schloop whose telephone number is (703)756-4597. The examiner can normally be reached Monday-Friday 8:30-5 ET.
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/ALLISON E SCHLOOP/Examiner, Art Unit 1683
/Robert T. Crow/Primary Examiner, Art Unit 1683