Detailed Office 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 .
37 C.F.R. § 1.114
A request for continued examination under 37 C.F.R. § 1.114, including the fee set forth in 37 C.F.R. § 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 C.F.R. § 1.114, and the fee set forth in 37 C.F.R. § 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 C.F.R. § 1.114.
Status of the Claims
Acknowledgement is hereby made of receipt and entry of the communication filed 23 July, 2026. Claims 1, 6-11, 13, and 14 are pending in the instant application.
37 C.F.R. § 1.98
The information disclosure statement filed 23 July, 2026, has been placed in the application file and the information referred to therein has been considered.
35 U.S.C. § 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.
Claims 7 and 8 are rejected under 35 U.S.C. § 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, regards as the invention. Two separate requirements are set forth under this statute: (1) the claims must set forth the subject matter that applicants regard as their invention; and (2) the claims must particularly point out and distinctly define the metes and bounds of the subject matter that will be protected by the patent grant.
Claims 7 and 8 reference a treatment method wherein “no more than 20 RNA determinants are measured” or “no more than 5 RNA determinants are measured”, respectively. First, the claims lack sufficient antecedent basis for measuring RNA determinants. Claim 1 simply references the measurement of CEACAM1 RNA quantities in a sample. No reference is made to measuring single or multiple RNA determinants. Second, it is not readily manifest which RNA determinants are being measured and how these correlate to any given viral infection. Appropriate correction is required.
35 U.S.C. § 112(a)
The following is a quotation 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.
New Matter
Claims 1, 6-11, 13, and 14 are rejected under 35 U.S.C. 112(a) 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. In re Rasmussen, 650 F.2d 1212, 211 U.S.P.Q. 323 (C.C.P.A. 1981).
The amended claims of the instant application are directed toward a method of treating a viral infection comprising measuring the amount of CEACAM1 levels in a subject, comparing said levels to an uninfected subject, and administering an antiviral to the subject if their levels exceed those of the uninfected subject, with the proviso that the viral infection excludes HIV-1, HBV, or HCV infections (claim 1). Claim 14 further specifies that the viral infection is caused by one of parainfluenza virus types 1-4, coronavirus 229E, NL63, or OC43, adenovirus types A-E, bocavirus types 1-4, IAV, IBV, metapneumovirus, rhinovirus types A-C, RSVA, RSVB, CMV, EBV, or an enterovirus (claim 14).
Perusal of the specification failed to provide support for any of these negative or positive limitations. There is no discussion with respect to CEACAM1 RNA levels and the viral infectivity status of any given patient. Those examples provided in the specification appear to be directed toward distinguishing between bacterial and viral infections by measuring certain RNA determinants. However, the specification fails to set forth any clear correlation between CEACAM1 RNA levels and the presence or absence of any particular virus. Accordingly, the claims are not adequately described and constitute new matter.
Enablement
Claims 1, 6-11, 13, and 14 are rejected under 35 U.S.C. § 112(a), 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. The amended claims of the instant application are directed toward a method of treating a viral infection comprising measuring the amount of CEACAM1 levels in a subject, comparing said levels to an uninfected subject, and administering an antiviral to the subject if their levels exceed those of the uninfected subject, with the proviso that the viral infection excludes HIV-1, HBV, or HCV infections (claim 1). Claim 14 further specifies that the viral infection is caused by one of parainfluenza virus types 1-4, coronavirus 229E, NL63, or OC43, adenovirus types A-E, bocavirus types 1-4, IAV, IBV, metapneumovirus, rhinovirus types A-C, RSVA, RSVB, CMV, EBV, or an enterovirus (claim 14). Claims 7 and 8 reference the measurement of 20, or 5, additional RNA determinants, respectively.
The legal considerations that govern enablement determinations pertaining to undue experimentation have been clearly set forth. Enzo Biochem, Inc., 52 U.S.P.Q.2d 1129 (C.A.F.C. 1999). In re Wands, 8 U.S.P.Q.2d 1400 (C.A.F.C. 1988). Ex parte Forman 230 U.S.P.Q. 546 (PTO Bd. Pat. App. Int., 1986). The courts concluded that several factual inquiries should be considered when making such assessments including the quantity of experimentation necessary, the amount of direction or guidance presented, the presence or absence of working examples, the nature of the invention, the state of the prior art, the relative skill of those in that art, the predictability or unpredictability of the art and the breadth of the claims. In re Rainer, 52 C.C.P.A. 1593, 347 F.2d 574, 146 U.S.P.Q. 218 (1965). The disclosure fails to provide adequate guidance pertaining to a number of these considerations as follows:
1) The specification fails to provide a direct correlation between CEACAM1 transcription levels and any given viral infection. The specification fails to provide any type of comparison involving the viral load of any given virus and CEACAM1 transcription levels. There is no data with respect to various disease outcomes (e.g., asymptomatic, symptomatic, symptomatic with required hospitalization, acute disease, chronic disease, latent disease, etc.) and CEACAM1 transcription levels. Studies involving influenza virus demonstrated that some viruses had no effect on CEACAM1 expression (Avadhanula et al., 2006; Ye et al., 2018). Avadhanula and colleagues reported that influenza virus infection had no effect on CEACAM1 expression (see left col., p. 1634). The study by Ye and associates demonstrated that CEACAM1 levels varied by influenza type. H5N1 infection increased CEACAM1 levels significantly whereas H1N1 infection did not significantly increase levels (see p. 6). An additional study by Potts et al. (2023) involving SARS-CoV-2 infection and COVID-19 demonstrated that CEACAM1 levels varied considerably depending upon the specific cell population and disease state. Hospitalized patients with severe disease displayed more pronounced elevation as compared to asymptomatic patients.
2) The specification fails to provide a direct correlation between the measurement of additional biomarkers (e.g., see Tables 1-6A, 15A, or 15B) and any given viral infection. Table 1 encompasses the following biomarkers: AIM2, ANKRD2, BMX, C19ORF59, CD177, CEACAM1, CLEC4D, CMPK2, EIF1AY, EIF2AK2, EPSTI1, FFAR3, GALM, IFITM3, INCA, IRF7, JARID1D, JUP, MT1G, MT2A, OTOF, PLSCR1, PSTPIP2, RGS1, TREML4, UTY, PARP12, PNPT1, TRIB2, UC003HRL.1, USP41, ZCCHC2, and TCONS_00003184-XLOC_001966. It is not readily manifest if any of these biomarkers are associated with a specific viral infection.
As previously set forth, patients (HIV-1-, HBV-, and HCV-negative) underwent two multiplex-PCR diagnostic assays from nasal swab samples: (i) Seeplex® RV15, for detection of parainfluenza virus 1, 2, 3, and 4, coronavirus 229E/NL63, adenovirus A/B/C/D/E, bocavirus 1/2/3/4, influenza virus A and B, metapneumovirus, coronavirus OC43, rhinovirus A/B/C, respiratory syncytial virus A and B, and Enterovirus, and (ii) Seeplex® PB6 for detection of Streptococcus pneumoniae, Haemophilus influenzae, Chlamydophila pneumoniae, Legionella pneumophila, Bordetella pertussis, and Mycoplasma pneumoniae. A microarray experiment was also performed to assess gene expression in subjects. RNA samples were hybridized to a Human Gene 1.0 ST Array which examines transcription of over 28,000 human genes. Software was utilized to assess various statistical parameters (e.g., area under the receiver operating curve (AUC)) and the purported ability of any given RNA determinant to measure viral or bacterial infections was determined. Perusal of the data failed to provide a direct correlation between any given RNA determinant and any specific virus. The data fails to correlate CEACAM1/PSTPIP2 expression with any specific virus.
The claims encompass the measurement of additional biomarkers (e.g., see Tables 2-6A, 15A, and 15B; claims 7 and 8). These tables contain 27 (CYBRD1,…,TCONS_12_000023; Table 2), 22 (CCL2,…,PPM1K; Table 3), 64 (APOBEC3C,…,IFIT3; Table 4), 7 (RSAD2,…,IFIT3; Table 5A), 3 (BTN3A3, RNF213, and PARP9; Table 6A), ~900 (TC14000584.hg.1,…,TC02001333.hg.1; Table 15A), and ~250 (TC0X002125.hg.1,…,TC0X001784.hg.1; Table 15B), respectively. Once again, the specification fails to provide a direct correlation between RNA determinant expression and any given viral infection. For example, if a sample comes back with elevated levels of CEACAM1, AIM, CYBRD1, and CCL2, what type of viral infection does this detect?
3) The specification fails to provide adequate guidance with respect to the establishment of predetermined biomarker levels for any given biomarker. As noted supra, an inordinate number of RNA determinants/biomarkers were screened using a chip array. However, the specification failed to provide adequate guidance with respect to the level of expression of any given determinant/biomarker and viral infection. If the skilled artisan detects a CEACAM1/PSTPIP2 transcript, what level would be predictive of any given viral infection? What constitutes a positive or negative sample? The disclosure is silent with respect to this issue.
4) The disclosure fails to provide adequate guidance with respect to any given antiviral treatment. In order to practice the claimed invention, the skilled artisan would need to know how any give RNA determinant/biomarker correlates with a specific viral infection. The specification states that patient samples were subject to parainfluenza virus 1, 2, 3, and 4, coronavirus 229E/NL63, adenovirus A/B/C/D/E, bocavirus 1/2/3/4, influenza virus A and B, metapneumovirus, coronavirus OC43, rhinovirus A/B/C, respiratory syncytial virus A and B, and Enterovirus testing. The skilled artisan would utilize different antiviral agents depending upon the virus. A coronavirus-specific antibody would most likely be ineffective against an RSV infection. Thus, the skilled artisan would need to understand the correlation between any given determinant and the specific virus in order to practice the claimed invention.
5) The claim breadth is excessive and encompasses an inordinate number of biomarker combinations. As noted supra, the claims encompass an inordinate number of combinations of RNA determinants/biomarkers. Tables 1-6A, 15A, and 15B comprise the following number of markers: 33 (AIM2,…,TCONS_00003184-XLOC_001966; Table 1), 27 (CYBRD1,…,TCONS_12_000023; Table 2), 22 (CCL2,…,PPM1K; Table 3), 64 (APOBEC3C,…,IFIT3; Table 4), 7 (RSAD2,…,IFIT3; Table 5A), 3 (BTN3A3, RNF213, and PARP9; Table 6A), ~900 (TC14000584.hg.1,…,TC02001333.hg.1; Table 15A), and ~250 (TC0X002125.hg.1,…,TC0X001784.hg.1; Table 15B), respectively. The claims are not limited to a specific combination of RNA determinants/biomarkers.
The claims are also not limited to any particular viral infection. The claim breadth encompasses any viral infection including dsDNA viruses (e.g., Adenoviruses, Herpesviruses, and Poxviruses), ssDNA viruses (e.g., Parvoviruses), dsRNA viruses (e.g., Reoviruses), ssRNA(+) viruses (e.g., Coronaviruses, Picornaviruses, and Togaviruses), ssRNA(-) viruses (e.g., Orthomyxoviruses and Rhabdoviruses), ssRNA-RT viruses (e.g., Retroviruses), and dsDNA-RT viruses (e.g., Hepadnaviruses). Once again, however, the disclosure fails to provide a direct correlation between expression levels of any given RNA determinant/biomarker and any specific viral infection.
6) The identification and development of suitable RNA determinants /biomarkers for the identification of viral infection has been challenging. For example, AIM2 is expressed in response to some viral infections (e.g., vaccinia virus), certain bacterial infections (e.g., Aspergillus, Listeria, and Mycobacterium), and in inflammatory responses (e.g., psoriasis, dermatitis, and arthritis) (Man et al., 2016). However, simply measuring elevated levels of AIM2 does not demonstrate that any given subject has a viral infection. Biserni et al. (2021) examined the prior art with respect to the development of suitable biomarkers for human adenovirus (HAdV) infection. While some putative serum markers were identified, nevertheless, there usefulness in diagnosis and clinical management remain to be demonstrated. For example, CRP and IL-10 were elevated during early infection. However, these serum markers are also elevated during bacterial infections.
7) The specification fails to provide any working embodiments. As set forth in the preceding paragraph, the development of suitable RNA determinants/biomarkers for viral detection has been challenging. While the disclosure describes a microarray experiment to assess gene expression in subjects, nevertheless, perusal of the data failed to provide a direct correlation between any given RNA determinant and any specific virus. The data fails to correlate CEACAM1/PSTPIP2 expression with any specific virus. Moreover, statistical analyses utilizing AUC has potential limitations including the following: 1) Distorted calibration; patient characteristics and disease rates may vary greatly between sources (local clinics, regional health centers, different countries, etc.). AUC is not reliable for imbalanced datasets. If the case has a significant class imbalance (e.g., fraud detection where fraud cases are rare), AUC can be misleading. A high AUC score may still fail at predicting positive cases. 2) AUC does not consider decision thresholds. It evaluates model performance across all classification thresholds; however, certain applications may require a specific threshold for decision-making. 3) Statistical overfitting; high AUC scores (close to 1.0) might be indicative of overfitting if the model has used one dataset. Medical data may contain measurement error; biomarker expression results may vary with assay location and kits. Moreover, this type of statistical analysis does not provide any insight pertaining to the sensitivity and specificity of an assay.
Accordingly, when all the aforementioned factors are considered in toto, the skilled artisan would reasonably conclude that undue experimentation would be required to practice the claimed invention.
Applicant traverses and submits the claimed invention is fully enabled. First, it was argued that various post-filing publications demonstrate that CEACAM1 is a broadly applicable marker of viral infection (Vitenshtein et al., 2016; Xue et al., 2018; Sharif-Askari et al., 2021). Applicant is reminded that publications providing information publicly first disclosed after the filing date generally cannot be used to show what was known at the time of filing. In re Gunn, 537 F.2d 1123, 1128, 190 U.S.P.Q. 402,405-06 (C.C.P.A. 1976); In re Budnick, 537 F.2d 535, 538, 190 U.S.P.Q. 422, 424 (C.C.P.A. 1976). See M.P.E.P. § 2164.05(a).
In any event, Vitenshtein and colleagues examined CEACAM1 induction in an in vitro assay involving non-immune cells. One experiment demonstrated that HCMV DNA induced CEACAM1 expression in HFF cells. Another assay demonstrated that infection of A549 cells by influenza led to increased CEACAM1 expression. However, this data did not examine CEACAM1 expression in patient samples and correlate said expression with viral load and disease state. Both Avadhanula et al. (2006) and Ye et al. (2018) provided a more complicated picture with respect to CEACAM1 expression during infection. Sharif-Askari and associates noted that CEACAM1 expression was upregulated in patient samples and that said expression was associated with the level of SARS-CoV-2 viral levels. However, the authors also concluded that the clinical relevance of this study required further confirmation. This is consistent with the teachings of Potts et al. (2023) involving SARS-CoV-2 infection and COVID-19 wherein it was demonstrated that CEACAM1 levels varied considerably depending upon the specific cell population and disease state. One of the limitations of the currently claimed method is that it fails to directly measure viral load and infectivity status. The assay does not measure viral RNA, DNA, or protein levels to confirm the presence or absence of an active viral infection.
Applicant further argues that the claims do not require the treatment of every viral disease. If the biomarker confirms the presence of a viral infection, an appropriate treatment regimen is initiated. The Examiner does not dispute this assessment. However, the claims are broadly directed toward virtually any viral infection. Thus, the claims and specification must provide a reasonable correlation between CEACAM1 RNA levels, tissue type, viral load, and disease state. Unfortunately, the specification does not meet these requirements. Applicant’s arguments have been carefully considered but are not deemed to be persuasive for the reasons of record set forth supra.
Correspondence
Any inquiry concerning this communication should be directed to Jeffrey S. Parkin, Ph.D., whose telephone number is (571) 272-0908. The Examiner can normally be reached Monday through Friday from 10:00 AM to 6:00 PM. A message may be left on the Examiner's voice mail service. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the Examiner are unsuccessful, the Examiner's supervisor, Michael Allen, Ph.D., can be reached at (571) 270-3497. Direct general status inquiries to the Technology Center 1600 receptionist at (571) 272-1600.
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Respectfully,
/JEFFREY S PARKIN/Primary Examiner, Art Unit 1671 22 September, 2026
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