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 .
Status of claims
Claims 1, 4-12 and 15-16 as amended on 7/07/2025 are pending and under examination in the instant office action.
Claim Rejections - 35 USC § 112
Enablement
Claims 1, 4-12 and 15-16 as amended are/remain 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.
Nature of the invention is a breath-based identification of patients having fusariosis or invasive fungal infection by Fusarium (page 1, lines 10-15).
Breadth of the claims is directed to treating a subject having fusariosis by administering an antifungal treatment upon diagnosing fusariosis as based on detection of several specific VOCs in a sample collected from the subject, wherein the list of the specific VOCs include all VOCs disclosed in specification table 2.
Prior art and/or state of the art teaches methods of diagnosing various diseases and health conditions in patients as based on detection from one to several specific VOCs in samples collected from the patients (for example: see US 6,221,026 (Phillipis)) including samples with from patients with fungal infections by Aspergillus (see abstract of WO 2015/187938 (Koo et al) and fungal infections by Mucorales and Rhizopus (see US 10,960,002 (Koo et al).
In particular, US 6,221,026 (Phillipis) teaches and discloses that relative abundances and frequencies of each and all VOC, that might be used for diagnosis purposes, are significantly variable parameters (see tables 1-2) from as low as 2 (table 2), wherein differences between groups of patients result from differences in relative severity of their conditions (col. 17, lines 49-41).
In particular, WO 2015/187938 (Koo et al) teaches that invasive aspergillosis is identified by detection in breath samples of the same VOCs as recited in the present claims including bergamotene, santalene and elemene (page 2, lines 10-20). Thus, the patients suspected in having fungal infections and being in need of diagnosis and antifungal treatment would be misdiagnosed; and these patients would not be differentiated as being having different infections.
In particular, US 10,960,002 (Koo et al) discloses identification of mucormycosis in patients or infection by Mucorales including Rhizopus by detection of the same VOCs as recited in the present claims including humulene, longipinene, isocomene, bisabolene and isocaryophyllene (caryophyllene isomer); for example: see col. 2, lines 3-18). US 10,960,002 (Koo et al) teaches that detection of at least two VOCs such as humulene and isocaryophyllene (isomer of claimed caryophyllene) indicates diagnosis of Rhizopus arrhizus (col. 2, lines 11-15). The instant claims recite detection of a specific combination of two VOCs including humulene and caryophyllene for diagnosis of presence of Fusarium (see list combination c in claims 1 , 4 and 12) and/or for diagnosis of presence of Fusarium verticilliodes (claim 12). Thus, the groups of patients having infection by Rhizopus and patients having infection by Fusarium are unlikely to be differentiated as being having different fungal infections. Therefore, they would be administered a relevant appropriate antifungal treatments.
Furthermore, production of VOCs by the claimed species of Fusarium; for example: caryophyllene, is a strain specific feature; and not all strains of Fusarium oxysporum are capable to produce this compound (see table 2 of the reference by Bitas et al (Frontiers in Microbiology. November 2015, vol. 6, article 1248, pages 1-14).
Thus, although detection of various VOCs as disease biomarkers has been known and practiced in the art, there is no satisfactory resolution of differentiating fungal diseases in in vivo systems such as invasive aspergillosis, mucormycosis and fusariosis as evidenced by the state of the art.
Now with respect to the specification disclosure:
First, the instant as-filed specification describes that not all claimed VOCs must be detected for the purpose of diagnosis but one or more VOCs can be used as previously was recited in the claims.
Further, the instant specification describes overlapping profiles of VOCs when detecting different infections including infection by Fusarium and by Scedosporium. The same compounds including presently claimed longipinene, gurjunene , isocomene, bergamotene, himachalane, bisabolene, cadinene are detected in samples with fungal species belonging to Fusarium and to Scedosporium (tables 1 and 2, pages 15-16).
Thus, there is no predictable and satisfactory resolution of differentiating of fungal diseases in in vivo systems such as invasive scedosporiosis and fusariosis as it is intended for the instant application and claims drawn to diagnosis of scedosporiosis.
The instant specification working examples, that describe indication of presence of species of Fusarium as based on detection of VOCs, are solely conducted in the in vitro system. There is no description in the as-filed specification of indication of Fusarium infection in the in vivo system as it would be based on detection of VOCs in breath samples of subjects having fusariosis or suspected to have fusariosis. Meanwhile, claimed-recited Fusarium biomarker VOC such as caryophyllene (claims 2 and 12) has inhibitory activity against Fusarium species including claim-recited species of F. proliferatum (see abstract of Liao et al (Pestic Biochem Physiol. 2024, 206, 106213, pages 1-12). Furthermore, production of caryophyllene is a strain specific feature; and not all strains of Fusarium oxysporum are capable to produce this compound (see table 2 of the reference by Bitas et al (Frontiers in Microbiology. November 2015, vol. 6, article 1248, pages 1-14).
Thus, there is no satisfactory resolution of problems with diagnosing and differentiating different fungal infection diseases as based on patient breath samples and/or headspace from cultures collected from patients in need in diagnosis and treatment fungal diseases. Consequently, state of the art, level of predictability and amount of guidance in specification raise a doubt as to enablement. Therefore, an "undue experimentation" would have been needed to use the claimed invention for diagnosis of fusariosis.
Response to Arguments
Applicant's arguments filed on 7/07/2025 have been fully considered but they are not all found persuasive.
The rejection of claims under 35 U.S.C. 101 has been withdrawn in view of current amened to the claims and applicants arguments as drawn to insertion of step of administering antifungal treatment to the subject having fusariosis (response pages 7-8).
With regard to claim rejection under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph (enablement requirement) Applicants argue that present claims require detection of all recited VOCs (not one or more as previously claimed) and detection of specific combinations (claims groups a, b, c and d) for detection of presence of each of 4 species of Fusarium.
The argument is not found convincing in view of specification disclosure. The instant specification working examples, that describe indication of presence of species of Fusarium as based on detection of VOCs, are solely conducted in the in vitro system. There is no description in the as-filed specification of indication of Fusarium infection in the in vivo system as it would be based on detection of VOCs in breath samples of subjects having fusariosis or suspected to have fusariosis. The state of the art teaches that abundances amd frequencies of VOCs in breath samples are variable parameters depending on severity of health conditions. For example: see US 6,221,026 (Phillipis) as explained above (table 1-2; col. 17, lines 49-41). Moreover, production of VOCs by the claimed species of Fusarium; for example: caryophyllene, is a strain specific feature; and not all strains of Fusarium oxysporum are capable to produce this compound (see table 2 of the reference by Bitas et al (Frontiers in Microbiology. November 2015, vol. 6, article 1248, pages 1-14). Thus, detection of all claim-recited VOCs is not a repeatable process for both in vivo and in vitro system.
The argument about detection of specific combinations of VOCs for diagnosis of a particular species of Fusarium is not considered persuasive. US 10,960,002 (Koo et al) teaches that detection of at least two VOCs such as humulene and isocaryophyllene (isomer of claimed caryophyllene) indicates diagnosis of Rhizopus arrhizus (col. 2, lines 11-15). The instant claims recite detection of a specific combination of two VOCs including humulene and caryophyllene for diagnosis of presence of Fusarium (see list combination c in claims 1 , 4 and 12) and/or for diagnosis of presence of Fusarium verticilliodes (claim 12). Thus, the groups of patients having infection by Rhizopus and patients having infection by Fusarium are unlikely to be differentiated as being having different fungal infections. Therefore, they would be administered a relevant appropriate antifungal treatments.
Thus, state of the art, level of predictability and amount of guidance in specification raise a doubt as to enablement. Therefore, an "undue experimentation" would have been needed to use the claimed invention for diagnosis of fusariosis.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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Vera Afremova
September 23, 2025
/VERA AFREMOVA/ Primary Examiner, Art Unit 1653