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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 2/2/2026 has been entered.
Status of Claims
Currently, claims 1-3, 5, 8-10, 13, 15, 22-23, 25-27, and 29-37 are pending in the instant application. Claims 25-27 are withdrawn from consideration as being drawn to a non-elected invention and claims 31-37 are newly added. All the amendments and arguments have been thoroughly reviewed but are deemed insufficient to place this application in condition for allowance. The following rejections are either newly applied, as necessitated by amendment, or are reiterated. They constitute the complete set being presently applied to the instant Application. Response to Applicant's arguments follow. This action is NON-FINAL.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Any rejection not reiterated is hereby withdrawn in view of the amendments to the claims.
Claim Rejections - 35 USC § 112
Claims 1-3, 5, 8-10, 13, 15, 22-23, and 29-37 are rejected under 35 U.S.C. 112(a) because the specification, while being enabling for a method of measuring the level of MT-ND3 mRNA in a human patient, detecting increased expression of MT-ND3 or MT-ND3 and MT-CO3 as compared to the level of MT-ND3 or MT-ND3 and MT-CO3 in healthy individuals, and diagnosing the patient as having hereditary angioedema, does not reasonably provide enablement for the claims as broadly written. 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 or 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 determination that a disclosure does not satisfy the enablement requirements and whether any necessary experimentation is undue. These factors have been described by the court in In re Wands, 8 USPQ2d 1400 (CA FC 1988). Wands states at page 1404,
“Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex parte Forman. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.”
The nature of the invention and the breadth of the claims:
The claims are broadly drawn to methods of measuring the expression level of MT-ND3 mRNA in any subject and making diagnostic and treatment decisions based on the level of the mRNA for HAE and HAE attack, where the undefined level of the mRNA is compared to any undefined control subject.
The invention is in a class of inventions which the CAFC has characterized as 'the unpredictable arts such as chemistry and biology" (Mycolgen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Federal Circuit 2001)).
The amount of direction/guidance and Presence/absence of working examples:
The specification defines subject as a human or a non-human mammal (instant specification p. 9).
The specification teaches, at page 40, a study to investigate novel RNA biomarkers of hereditary angioedema, wherein an analysis was performed comparing the circulating small RNAs present in plasma samples obtained from 39 patients with HAE to samples obtained from 3 healthy individuals. The specification teaches the abundance of each of the detected RNAs were compared between the samples from healthy individuals and patients having HAE. The specification teaches as shown in Figure 1, RNA transcripts of MT-ND3 and MT-CO3 were higher in samples from human patients having HAE as compared to samples form healthy individuals in the initial RNASeq as well as by RT-qPCR analysis. However, the lone example in the specification, Example 1, and the accompanying Figure 1, are limited to hereditary angioedema (HAE) in human subjects compared to healthy individuals. The specification does not provide any guidance as to whether the level of MT-ND3 can identify a subject as at risk of HAE attack by simply measuring the level of MT-ND3, or that any undefined control comparison would yield the same results. The specification does not teach whether the levels of MT-ND3 are increased, decreased, or remain unchanged so as to be able to identify any subject as having HAE or at risk of HAE attack. The specification does not teach analysis of MT-ND3 expression in non-human subjects.
The state of the prior art and the predictability or unpredictability of the art:
The art teaches that expression levels of can be inconsistently and unpredictably associated with various diseases.
Regarding miRNA expression, Ha teaches that conserved miRNAs does not necessarily exhibit the same expression levels or patterns in different species (Ha et al. Biochim Biophys Acta 2008 Nov 1779(11): 735-742, Abstract). Although sequence conservation of miRNAs and target genes may suggest conservation of expression patterns and functions, this assumption does not hold true for many conserved miRNAs (Ha p. 4). Moreover, developmental variation may exist among different species (Ha p. 5). Although the regulatory mechanisms for miRNAs and their target recognition are highly conserved between species, expression variation of miRNAs and their targets exists among different species and even closely related species (Ha p. 5).
The level of skill in the art:
The level of skill in the art is deemed to be high.
The quantity of experimentation necessary:
The quantity of experimentation in this area is large since there are a large number of parameters which would have to be studied to enable the skilled artisan to use the method as broadly claimed. The claims are directed to a correlation between HAE diagnosis or risk of attack in any subject, based on undefined levels of MT-ND3 RNA levels to undefined controls. It is unpredictable that a skilled artisan could identify any disease other than hereditary angioedema based on the expression levels of MT-ND3 in a human subject. While the specification provides guidance for a correlation between the expression level of MT-ND3 and HAE in humans, it does not provide guidance for the broad scope of the claims. To practice the invention as broadly as it is claimed, the skilled artisan would have to perform additional unpredictable and undue experimentation of expression levels of MT-ND3 in any subjects as broadly defined, which would require a large amount of inventive effort with no predictable expectations of success.
Thus given the broad claims in an art whose nature is identified as unpredictable, the large quantity of research required to define these unpredictable variables, the lack of guidance provided in the specification, the absence of a working example and the negative teachings in the prior art balanced only against the high level of skill in the art, it is the position of the examiner that it would require undue experimentation for one of ordinary skill in the art to perform the method of the claims as broadly written.
Response to Arguments
The response traverses the rejection and asserts that the claims have been amended. This argument has been thoroughly reviewed but was not found persuasive for the reasons made of record above.
Claim Rejections - 35 USC § 103
Claims 1-2, 5, 8-10, 13, 15, 22-23, and 29-37 are rejected under 35 U.S.C. 103 as being obvious over Lopez-Lera (Lopez-Lera et al; Orphanet Journal of Rare Diseases, 8:77, 2013; pages 1-12; cited in the IDS dated 6/4/2019) in view of Cicardi (Cicardi et al; NEJM, vol 363, 2010, pages 532-541).
Lopez-Lera teaches whole genome RNA expression of PBMCs in type I HEA families (claim 4, 5, 10). Lopez-Lera teaches measuring gene expression using microarray based gene expression analysis (claim 9) to analyze whole genome RNA expression (page 2, col 2). Lopez Lera teaches that MT-ND3 expression was elevated as compared to control individuals (supplemental table 2, cell number 2948). With regard to claim 2, although the claim recites a “set consists of 2-10 RNA biomarkers”, claim 1 recites “comprising” which allows for analysis of more RNA than that which is in any particular “set”. Lopez Lera does not teach treatment of patients with HAE with icatibant, however Cicardi teaches that icatibant was successful in improvement of symptoms of patients with HAE. Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date to have treated patients taught by Lopez Lera, as taught by Cicardi with a reasonable expectation of success.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Lopez-Lera in view of Cicardi, and further in view of Gao (Gao et al; J Allergy Clin Immunology, 2014, AB32 abstract 117; cited in the IDS dated 6/4/2019).
The teachings of Lopez Lera and Cicardi are set forth above and incorporated herein. Although Lopez-Lera teaches analysis in PBMCs rather than plasma or serum, Gao teaches analysis of plasma for circulating extracellular nucleic acid in HAE patients. Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date to modify the method of Lopez-Lera and Cicardi, and measure expression in plasma as taught by Gao for the purpose of analyzing gene expression of circulating nucleic acids in HAE patients.
Conclusion
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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/JEHANNE S SITTON/Primary Examiner, Art Unit 1682
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