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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in
37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on February 9, 2026 has been entered.
Claim Status
Claim listing filed on February 9, 2026 is pending. Claims 13, 16, and 23-48 are canceled. Claims 1, 7-8, and 12 are amended. Claims 49-55 are new. Claims 1-12, 14-15, 17-22, and 49-55 are examined upon their merits.
Withdrawn Objections and Rejections
The objection to Claim 6 is withdrawn, because Examiner was mistaken and no chemical names are repeated.
The rejection of Claims 7-8 and 12 under 35 U.S.C. 112(b) as being indefinite are withdrawn in view of Applicant’s amendments. In particular, amended Claim 7 recites “decreases expression of one or more markers of viability…as compared to a subject not receiving said composition.” This relative terminology is definite as the decrease is relative to a subject with AML as defined in Claim 1 that does not receive the composition comprising a UBE2N inhibitor. Note, the broadest reasonable interpretation of “decreases” is any reduction (even a non-significant change). Amended Claim 12 no longer recites the indefinite term “resensitizes.”
The rejection of Claims 1-11, 14-15, and 17-22 under 35 U.S.C. 103 as being unpatentable over Starczynowski WO 2018/081361 in view of Smith WO 2018/081738 is withdrawn in view of Applicant’s amendments. Neither Starczynowski nor Smith teach “identifying a subject with AML as having a classification of UBE2N-dependent AML or UBE2N-resistant AML” and administering a UBE2N inhibitor “to a subject classified as having UBE2N-dependent AML” as required by amended Claim 1. Note, Claims 3-4 recite wherein the AML subtype comprises AML-M4 or AML-M5, and Claims 49-50 define wherein the UBE2N-dependent AML is a myelomonocytic or monocytic AML subtype comprising AML-M4 or AML-M5. It is interpreted that not all AML-M4 or AML-M5 subtypes are UBE2N-dependent. Of the UBE2N-dependent AML subtypes, some may be AML-M4 or AML-M5, but not all AML-M4 or AML-M5 subtypes are inherently UBE2N-depedent. This interpretation is supported by instant specification Fig. 16 which shows that both Group 1 (UBE2N-dependent signature low) and Group 2 (UBE2N-dependent signature high) comprise patients that are both positive and negative for AML-M4 and AML-M5 subtypes.
The rejection of Claims 1 and 12 under 35 U.S.C. 103 as being unpatentable over Starczynowski WO 2018/081361 in view of Smith WO 2018/081738, and further in view of Guerra et al. Best Pract Res Clin Haematol. May 2019 as evidenced by Dana-Farber 2025 is withdrawn in view of Applicant’s amendments. Guerra and Dana-Farber 2025 fail to cure the deficiencies of Starczynowski and Smith outlined above.
Claim Objections (New, necessitated by amendment)
Applicant is advised that should Claim 1 be found allowable, Claim 55 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. Claim 1 recites identifying a subject with AML as having a classification of UBE2N-dependent AML or UBE2N-resistant AML followed by administering a UBE2N inhibitor to a subject classified as having UBE2N-dependent AML. Claim 55 recites prior to administering the treatment, classifying the subject as having UBE2N-dependent AML or UBE2N-resistant AML. It is understood that the identifying/classifying in Claim 1 must occur prior to the treatment since the classification of UBE2N-dependent AML dictates which subjects receive the treatment. Therefore, Claims 1 and 55 are substantial duplicates. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim Rejections - 35 USC § 112 (New, 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.
Claims 1-12, 14-15, 17-22, and 49-55 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 “identifying a subject with AML as having a classification of UBE2N-dependent AML or UBE2N-resistant AML.” The terms “UBE2N-dependent AML” and “UBE2N-resistant AML” are not clearly defined in the specification nor understood in the art prior to filing. Because UBE2N-dependent AML and UBE2N-resistant AML classifications have unclear definitions, it is also unclear how to identify a subject with these AML subtypes. The specification teaches that 26 PDX AMLs showed a range of sensitivities to UBE2N inhibition, and a hierarchical clustering system was applied to categorize the PDX AMLs into two distinct groups: those that were sensitive to UBE2N inhibition termed “UBE2N-dependent” and those that were resistant to UBE2N inhibition termed “UBE2N-resistant” (paragraph [00194 and Fig. 13A). It is important to note that hierarchical clustering is deterministic and data-driven, and any change to the dataset such as adding or removing points will change the arrangement of the resulting clusters. Therefore, performing a hierarchical clustering on different datasets does not provide clear boundaries as to which subjects are classified as UBE2N-dependent AML or UBE2N-resistant AML because the classifications could change based on the data evaluated (see wherein reference to a variable object can render claims indefinite in MPEP § 2173.05(b).II). Expression levels of the top 50 genes that are differentially expressed between UBE2N-dependent and UBE2N-resistant PDX samples were evaluated (paragraph [00196] and Figs. 13E-13F and Tables 7-8); however, this data does not provide guidance on how to identify subjects as having UBE2N-dependent AML or UBE2N-resistant AML. Similarly, an unsupervised hierarchical clustering analysis of RNA sequencing data from the Cancer Genome Atlas and Leucegene databases was performed to sort patients into two distinct groups: Group 1 “Low UBE2N-dependent signature” and Group 2 “High UBE2N-dependent signature” (paragraph [00197] and Figs. 13G-13I); however, this data does not provide guidance on how to identify subjects as having UBE2N-dependent AML or UBE2N-resistant AML. For these reasons, “UBE2N-dependent AML” or “UBE2N-resistant AML” are indefinite classifications as is the method of identifying subjects classified as having UBE2N-dependent or UBE2N-resistant AML, and Claims 1-12, 14-15, 17-22, and 49-55 are rejected.
Claim 12 recites “wherein the subject has been treated previously with one or more BCL2 inhibitor” (emphasis added). There are two subjects defined in Claim 1: (1) “identifying a subject with AML as having a classification of UBE2N-dependent AML or UBE2N-resistant AML” and (2) administering a UBE2N inhibitor to “a subject classified as having UBE2N-dependent AML” (emphasis added). The first subject can have UBE2N-dependent AML or UBE2N-resistant AML, and the second subject has UBE2N-dependent AML and is administered therapy. Therefore, Claim 12 can be interpreted in two ways which makes the claim indefinite. First, a subject has been treated with a BCL2 inhibitor prior to AML subtype classification, or second, a subject who has been classified as having a UBE2N-resistant AML has been treated previously with a BCL2 inhibitor prior to administration of the UBE2N inhibitor. Claim 12 is rejected for indefiniteness. Note, it is clear that the subject of Claims 7 and 20 is the subject receiving treatment administration (second subject defined in Claim 1), and the subject of Claims 21-22, 51, and 55 is the subject identified as having an AML subtype (first subject defined in Claim 1). Note, it is interpreted that the further administration steps recited in Claims 14-15 and 17 solely apply to the subject classified as having UBE2N-dependent AML who is administered the UBE2N inhibitor (first subject defined in Claim 1).
Claim 51 recites “UBE2N-dependent genes” and this term is not defined in the specification nor understood in the art prior to filing. Fig. 13E lists exemplary UBE2N-depedent genes (paragraph [00160]); however, these genes only represent the top 50 genes that were differentially expressed between UBE2N-dependent and UBE2N-resistant PDX AMLs and thus is not a complete list of UBE2N-depedent genes (paragraph [00199]). The metes and bounds of what is considered a “UBE2N-dependent gene” is unclear, and Claims 51-54 are rejected. Importantly, “UBE2N-dependent genes comprise genes associated with TLR signaling, complement and coagulation cascades, and/or production of proinflammatory cytokines” as recited in Claim 53 is still unclear; because UBE2N-dependent genes are undefined, the UBE2N-dependent genes associated with the recited functions are also undefined.
Claim 52 recites wherein a classification of UBE2N-dependent AML comprises higher expression levels of two or more UBE2N-dependent genes as compared to baseline and/or UBE2N-resistant AML. This limitation includes indefinite relative terminology, because it is unclear to what the “higher expression levels” are being compared (MPEP § 2173.05(b)). The expression levels of UBE2N-dependent genes in subjects with UBE2N-resistant AML are not defined, nor is the term “baseline” defined. Is “baseline” the expression levels of UBE2N-dependent genes of healthy subjects? Claim 52 is rejected for indefinite relative terminology.
Claim 53 is indefinite because it recites the abbreviation “TLR” without defining the abbreviation in the claims. For the purpose of compact prosecution, “TLR” is interpreted as “toll-like receptor,” but appropriate clarification is required.
Claim 54 recites wherein a classification of UBE2N-dependent AML comprises elevated expression and/or activity of genes and/or proteins associated with two or more immune signaling pathways. “Elevated expression and/or activity” is indefinite relative terminology because it is unclear to what the elevation is being compared (MPEP § 2173.05(b)). “Genes and/or proteins associated with two or more immune signaling pathways” are interpreted as distinct from the UBE2N-dependent genes defined in Claim 51, and the broadest reasonable interpretation is that it can comprise at least two genes or proteins that are each known to be associated with a different immune signaling pathway.
Note, it is of record that “treating” and “treatment” are defined in the specification as encompassing both therapeutic treatment (comprising relieving or curing an established disease) and prophylactic treatment (comprising preventing a disease from occurring) (paragraph [0043]). However, Claim 1 recites a method of treating wherein subjects with AML are identified and administered treatment. Therefore, it is clear that the subjects of Claim 1 have established AML, and “treating” in this context refers to therapeutic treatment not prophylactic treatment.
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 1-12, 14-15, 17-22, and 49-55 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 claims contain 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.
Claim 1 recites a method comprising “identifying a subject with AML as having a classification of UBE2N-dependent AML or UBE2N-resistant AML” and administering a UBE2N inhibitor to a subject classified as having a UBE2N-dependent AML. Claims 51-53 are directed to analyzing a sample from the subject to determine expression levels of two or more UBE2N-dependent genes wherein high expression levels classify the AML as UBE2N-depedent. Claim 54 defines wherein a UBE2N-dependent AML comprises elevated expression and/or activity of any genes or proteins associated with two or more immune signaling pathways.
In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant has possession of and what Applicant is claiming. In order to provide adequate written description and evidence of possession of this claimed method, the specification must provide sufficient distinguishing identifying characteristics of the method.
The specification teaches that 26 PDX AMLs showed a range of sensitivities to UBE2N inhibition, and a hierarchical clustering system was applied to categorize the PDX AMLs into two distinct groups: those that were sensitive to UBE2N inhibition termed “UBE2N-dependent” and those that were resistant to UBE2N inhibition termed “UBE2N-resistant” (paragraph [00194 and Fig. 13A). It is important to note that hierarchical clustering is deterministic and data-driven, and any change to the dataset such as adding or removing points will change the arrangement of the resulting clusters. Therefore, this experimental example does not provide standard definitions of “UBE2N-dependent” and “UBE2N-resistant” such that one of ordinary skill would understand that the inventors had possession of a method of identifying subjects with UBE2N-depedent AML or UBE2N-resistant AML, because, based on this experiment, these classifications are moving targets that lack definite criteria. Further, mimicking this experiment would require administration of a UBE2N inhibitor prior to subtype classification in order to determine which subjects are UBE2N-depedent which performs the two procedural steps of Claim 1 in the opposite order (i.e. administering UBE2N inhibitor prior to classification rather than administering UBE2N inhibitor as a result of classification).
Expression levels of the top 50 genes that are differentially expressed between UBE2N-dependent and UBE2N-resistant PDX samples were evaluated (paragraph [00196] and Figs. 13E-13F and Tables 7-8). Further, an unsupervised hierarchical clustering analysis of RNA sequencing data from the Cancer Genome Atlas and Leucegene databases was performed to sort patients into two distinct groups: Group 1 “Low UBE2N-dependent signature” and Group 2 “High UBE2N-dependent signature” (paragraph [00197] and Figs. 13G-13I). These experiments show broad correlation trends using heatmaps across 50+ genes without any specific methodology that can be used to classify subjects as having UBE2N-depedent AML or UBE2N-resistant AML based on their gene signatures. In contrast, Vakiti et al. StatPearls 2024 teaches how AML subtypes are classified by specific genetic abnormalities (such as mutated NPM1) or by cellular morphology (M0-M7) (“Staging”). The criteria for the known methods of subtyping AML are specific and concrete such that a practitioner could consistently and accurately diagnose patients with an AML subtype and treat them accordingly. The instant specification does not teach specific criteria required for identifying subjects having UBE2N-depedent AML or UBE2N-resistant AML. For example, no definition is provided wherein a subject having “X” gene above “Y” expression threshold is categorized as UBE2N-depednent. Consistently and accurately classifying subjects as UBE2N-dependent is of the utmost importance in the claimed method as the subtype classification dictates whether or not to administer treatment. Therefore, Claims 1-12, 14-15, 17-22, and 49-55 are rejected for insufficient written description of the claimed treatment method.
Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115).
Claims 1-12, 14-15, 17-22, and 49-55 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
MPEP § 2164.01(a) states that 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”. These factors include, but are not limited to:
A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01.
The breadth of the claims and nature of the invention:
The nature of the invention is complex, encompassing a method comprising “identifying a subject with AML as having a classification of UBE2N-dependent AML or UBE2N-resistant AML” and administering a UBE2N inhibitor to a subject classified as having a UBE2N-dependent AML (Claim 1). Claims 51-53 are directed to analyzing a sample from the subject to determine expression levels of two or more UBE2N-dependent genes wherein high expression levels classify the AML as UBE2N-depedent. Claim 54 defines wherein a UBE2N-dependent AML comprises elevated expression and/or activity of any genes or proteins associated with two or more immune signaling pathways.
When analyzing enablement, the claims are analyzed with respect to the teachings of the specification and are to be "given their broadest reasonable interpretation consistent with the specification." See MPEP 2111 [R-5]; Phillips v. AWH Corp., 415 F.3d 1303, 75 USPQ2d 1321 (Fed. Cir. 2005); and In re Hyatt, 211 F.3d 1367, 1372, 54 USPQ2d 1664, 1667 (Fed. Cir. 2000). Applicant always has the opportunity to amend the claims during prosecution, and broad interpretation by the examiner reduces the possibility that the claim, once issued, will be interpreted more broadly than is justified. In re Prater, 415 F.2d 1393, 1404-05, 162 USPQ 541, 550- 51 (CCPA 1969).
The state of the prior art and level of predictability in the art:
The level of predictability in the art depends, most importantly, on whether the claimed invention can be practiced by one of ordinary skill in the art. Vakiti et al. StatPearls 2024 teaches the standard procedures for subtyping AML. The French-American-British system classifies AML into 8 subtypes (M0-M7) based on cellular morphology (“Staging”). The World Health Organization revised the classification of AML to subtype based on specific genetic abnormalities (“Staging”). These teachings demonstrate, even after the effective filing date of the instant invention, how AML subtyping is based on specific and constant criteria wherein a skilled practitioner can diagnose an AML subtype with accuracy and reproducibility.
The state of the art does not teach methods of identifying subjects as having UBE2N-dependent AML or UBE2N-resistant AML, and there is no support in the disclosure leading one of ordinary skill to use this method with a reasonable expectation of success in classifying UBE2N subtypes with accuracy and reproducibility as is demonstrated by current AML subtyping standards.
Level of skill in the art:
The level of skill would be high encompassing oncology, pathology, genetics, etc.
Amount of direction provided by inventor and the existence of working examples:
The relevant teachings from the specification (Example 7) are detailed in the 112(b) indefiniteness and 112(a) written description rejections above. The specification offers no guidance for criteria that must be met to classify subjects as having either UBE2N-depenedent AML or UBE2N-resistant AML. Further, the specification does not teach which genes and/or proteins are required to be elevated and to what threshold to diagnose a subject with UBE2N-dependent AML. Considering that accurate identification of a subject having UBE2N-depedent AML is necessary to administer an effective treatment, the claimed method of treatment cannot be used with a reasonable expectation of success without undue experimentation. A person having ordinary skill in the art would have to make a substantial inventive contribution in order to determine how to identify AML subjects as either UBE2N-depednent or UBE2N-resistant in a way that is constant, reliable, and accurate (i.e. not context-specific as is exemplified by the specification) in order to practice the claimed method with a reasonable expectation of success. Applicant remarks filed 02/09/2026 state that “classifying a subject as having UBE2N-depednent AML is an important aspect developed by the present inventors, without which treatment via a UBE2N inhibitor could not be expected to have efficacy” (emphasis added). This statement further supports the importance of identifying subjects with UBE2N-depednent AML because the claimed treatment (UBE2N inhibitor administration) has no expectation of successfully treating AML subjects of other subtypes.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure:
In light of the unpredictability surrounding the claimed subject matter, the breadth of the claimed invention’s intended use, and the lack of adequate guidance, one wishing to practice the presently claimed invention would be unable to do so without engaging in an unknown quantity of experimentation. Given that the nature of the claims is in vivo treatment, a person having ordinary skill in the art would have to perform multiple further experiments, in human clinical trials or in animal models, that are predictive of accurately identifying subjects with UBE2N-dependent AML and effectively treating said subjects with a UBE2N inhibitor in order to demonstrate the invention could be used with a reasonable expectation of success. The amount of experimentation required for enabling guidance goes beyond what is considered ‘routine' within the art, and constitutes undue further experimentation in order to use the treatment with a reasonable expectation of success. The instant specification does not enable the invention to identify a subject with AML as having a classification of UBE2N-dependent AML or UBE2N-resistant AML, and Claims 1-12, 14-15, 17-22, and 49-55 are rejected.
Note, the claims could be amended to potentially overcome the 35 USC § 112 rejections of record by identifying subjects with UBE2N-dependent AML by the presence of a UBE2N-dependent gene signature wherein the gene signature is a defined set of genes at a defined expression level based on the data from Example 7 of the specification. This potential amendment could direct the claims to a definite and enabled method of identifying UBE2N-dependent AML in subjects.
Conclusion
No claim is allowed.
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/SARAH COOPER PATTERSON/Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675
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