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 .
Election/Restrictions
Applicant's election with traverse of Group I and species “at least one gene selected from the following genes: GNLY, S100A9, C3AR1, ADGRE3, CX3CR1, IFIH1, OAS2, OAS3” which are “at least one gene selected from the family of genes encoding molecules involved in the innate immune system” in the reply filed on 9/18/2025 is acknowledged. The traversal is on the ground(s) that it would not require undue burden to examine all groups and species together. This is not found persuasive because the examination of products and methods together raises at least undue burden of examination burden where different analysis under at least 101 is required for the different statutory classes of claims. Furthermore, there is a clear search burden to examine all species together as this involves the search and consideration of hundreds of possible combinations and sub-combinations of genes. Rejoinder of species will be considered upon a finding of allowable subject matter.
The requirement is still deemed proper and is therefore made FINAL.
Claim Rejections - 35 USC § 112
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.
Claims 1-11 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.
This is a rejection for new matter.
The newly added “comparing” and “classifying” steps in claims 1-11 are contain new matter. Furthermore, the newly added “adjusting” steps in claims 2-5 are new matter.
The response points to paragraphs 66-68, 88-90 and Tables 4-7 as providing basis for the amended claims.
¶66-68 discuss normalizing gene expression, and paragraph 68 discusses that the normalized expression from the patient is compared to the normalized expression of a reference sample. This provides basis for the comparing portion of the comparing step, but it does not provide basis for the thereby statement which recites “thereby obtaining a comparative value.” There is no written description as to how the “comparing” results in a “comparative value.”
There is clearly an implication in the specification that the disclosed methods will be used to “classify” a patient or to determine an increased risk relative of healthcare associated infection (HCAI) to a patient population. However, there is no express or implicit description of doing so using a “comparative value,” which could be any possible calculated or derived value or even a categorical value such as zero for equal, -1 for less than, and +1 for greater than.
¶88-90 discuss data analysis from a study where CD177 was measured at different times and the incidence of healthcare-associated infection before D30 was evaluated. Universal logistic regression was implemented in order to predict the risk of incidence of a healthcare associated infection before D15. The disclosure teaches “the power of values predicted by logistic regression to distinguish between healthcare associated infection and lack thereof was quantified by area under the curve of the receiver operating characteristic.”
The tables present AUC observed.
None of these teach comparing a normalized value to another value (as set forth in the comparing step) and thereby obtaining a comparative value.
The AUC measures the predictive power of a classifier. In the example, this was values predicted by a logistic regression, which was not disclosed in the example. There is no description of how the logistic regression is related to the claimed “comparative value” or how to calculate or obtain the comparative value. There is no express, inherent or implied step of comparing two values and obtaining a comparative value, which in a next step is used to classify a patient when the comparative value meets or exceeds a decision threshold obtained from a “reference population.”
The description does not address obtaining a “comparative value” and comparing it to a “threshold” to classify a patient. There is, in particular, no written description to suggest possession of a method wherein comparing a normalized expression to a pre-determined reference value or the expression of the same gene in a reference sample results in a “comparative value” and then using that “comparative value” to classify a patient at risk. Further, there is no disclosure of any pre-determined threshold in the cited paragraphs.
Furthermore, with regards to claims 2-5, ¶45 and table 2 teach biomarkers which can be used “in combination” with CD177, but does not provide any written description as to the claimed adjusting of any particular value using the biomarkers in table 2 (or those consonant with the election), and in particular none of the five different values that are recited in claims 2-5. Table 6 provides performance of the measurement of CD177 in combination with one or more other markers (multivariate analysis). There is no written description of how the values were combined in the multivariate analysis, nor what value was “adjusted” using the values of the one or more additional genes or how it was adjusted. There is no general written description to support the “adjusting” that is set forth in amended claims 2-5.
Written description of amended claims may be either express, inherent or implied. Here, there is no express basis for the limitations, nor is the basis inherent. Although there is no express basis for “classifying the patient” this is implied by the specification, however it is not employed HOW this classifying occurs, namely it is not implied that a “comparative value” is obtained and compared to a decision threshold.
Applicant argues that a person having ordinary skill in the art reading the specification would have readily appreciated that the AUC[Wingdings font/0xE0]ROC approach is universally recognized as involving classification based on a predetermined decision threshold. The AUC approach is a measure of a classifier, which, in the instant specification was obtained either by logistic regression or multivariable analysis. An ROC curve can be used to find a classification threshold for a classifier that was examined; and in this case there is no disclosure of the classifier and there is no disclosure that the classifier obtains a “comparative value” by comparing to a reference (as opposed to, for example by using a regression model), and there is no written description of a multistep process in which comparing results in obtaining a comparative value which is then compared to a threshold. There is not even written description that the step of identifying the classification threshold was carried out. Developing an ROC and calculating the AUC does not inherently determine a threshold.
Applicant cites two websites available as evidence to support this position, neither of which was provided, nor is it immediately clear from applicant’s arguments that these were even available in the prior art. They have not been considered.
Therefore, the claims are rejected for having new matter.
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 1-11 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.
With regard to claim 1, it is unclear how “comparing” two values results in “obtaining a comparative value.” Comparison is an observation, but nothing about comparing inherently results in a value as the recited “thereby” clause implies. It is not clear what is required by the claim to obtain a “comparative value” or what the comparative value is.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-11 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a law of nature and an abstract idea without significantly more.
The claim(s) recite(s) determining risk of incidence of a healthcare-associated infection via measuring the expression of CD177 in a biological sample. Thus, the claims describe a relationship between CD177 expression and risk of the infection. This is a naturally occurring correlation of the type which the courts have recognized as a law of nature judicial exception.
The claims further recite that the measured expression is “normalized” which is a mathematical concept abstract idea.
The claims further recite “comparing” and “classifying” which are mental process abstract ideas.
The dependent claims further recite “adjusting” a value or values which is also a mathematical process and mental process abstract idea.
This judicial exception is not integrated into a practical application because the claims only have additional steps related to necessary data gathering. These steps do not apply or use the judicial exception in any way. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because methods for determining expression were well established routine and conventional. See specification p. 71 which discusses “numerous” methods that existed for determining gene expression including commercially available RT-PCR techniques.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 6, 7, 8, 9, 10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Demaret et al. (2016) in view of Hall et al. (WO 2018/060739 A2).
Demaret teaches a method that includes a step of measuring the expression of CD177 in a biological sample from a patient and normalizing the expression value (p. 124, see microarray analysis).
Demaret teaches comparing the normalized expression value to a pre-defined reference value or to the expression value of the same gene in a reference biological sample, thereby obtaining a comparative value. Namely, Demaret teaches comparing the values obtained in septic patients to healthy controls (same gene in reference biological sample; Section 2.4).
Damaret teaches that patients with sepsis have increased levels of CD177 (Section 3.2).
Damaret does not teach classifying a patient as at risk when the comparative value meets or exceeds a predetermined threshold established from a reference population. Demaret teaches a study that identifies CD177 as a marker expressed in sepsis patients compared to healthy controls, but does not teach applying this finding as a diagnostic.
Hall teaches methods for diagnosing a systemic inflammatory condition by determining the amount of an inflammation biomarker in a sample, including CD177, comparing the presence and/or amount of the marker to a reference value (i.e. predetermined threshold), and thereby determining a subject has a systemic inflammatory condition or risk of developing a systemic inflammatory condition (see p. 11).
Like Demaret, Hall undertakes studies to determine markers that are differentially expressed among phenotypes (Example 1; p. 175 and following). Hall identified CD177 as being differentially expressed in inflammation (Table 1; p. 178). These steps are similar to those carried out in Demaret. Hall teaches using ROC analysis to determine the sensitivity and specificity with which biomarkers discriminate between patients (p. 188 and following).
Hall teaches a diagnostic method that includes steps of comparing normalized expression to a reference value and thereby and classifying determining whether the patient has the relevant condition. Hall teaches that detecting increase in abundance compared to healthy individuals indicates patients having systemic inflammatory condition (p. 31, 6th ¶; p. 32, 4th¶). Thus, Hall teaches classifying the patient as having risk for inflammatory disorder when the expression (which is considered the “comparative value” of the claim) exceeds that of healthy individuals (i.e. a predetermined threshold).
Therefore, it would have been obvious to have modified the method taught by Demaret so as to have applied the finding that CD177 is upregulated in sepsis so as to have used it to diagnose sepsis by detecting expression of CD177 in a sample, comparing it to a reference value and classifying the patient as having sepsis or risk of sepsis relative to the comparison, as exemplified by Hall. One would have been motivated to do so in order to identify sepsis individuals for further treatment, and one by the exemplification by Hall that markers found to be differentially expressed in immune states can be used to diagnose risk for the immune state via comparison with a threshold value.
Instant claim 1 has an intended use in the preamble, and the method taught by Demaret could be used as intended. Instant claim 1 sets forth a preamble that does not distinguish the method of the instant invention from the claimed invention. Furthermore, the “thereby” clause that ends the claim sets forth what has happened but does not require any action that distinguishes from the reference. In particular the “classifying” step does not set forth what the subject is “at risk” for. Therefore, classifying the subject as “at risk” of developing sepsis meets the classifying step of claim 1. As currently drawn, claim 1 does not require, in an active process step, classifying the subject as “at risk” (increased or decreased) for healthcare-associated infection. The active process step merely requires “classifying the subject as at risk when…” and states that the such classifying “thereby” accomplishes the risk.
Regarding claim 6, the reference teaches a blood sample (section 2.2).
Regarding claims 7 and 10, the expression was measured at the mRNA level using hybridization to a microarray (section 2.3).
With regard to claims 8 and 9, Hall teaches RT-PCR and sequencing as techniques for measuring biomarkers (p. 21, 3rd paragraph).
Claim(s) 2-5 and 11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Demaret in view of Hall as applied to claims 1, 6, 7, 8, 9, 10 above, and further in view of Khatri et al. WO 2016/145426.
The teachings of Demaret in view of Hall as they are applied to claim 1, from which claims 2-5 depend are given previously in this Office action and are fully incorporated here.
Regarding claims 2, 3, 4 and 5, Demaret teaches measuring nucleic acid expression using a microarray, namely the Affymetrix U133 2.0 plus microarray (see p. 124), which inherently has upon it at least one gene selected from the family of genes encoding molecules involved in the innate immune system, including each of the elected genes. By measuring expression of genes on the microarray, expression of each of the elected genes was measured. The presence of the elected genes on the microarray was confirmed by reviewing the NCBI platform data for the U133 2.0 plus microarray, GPL570.
Demaret does not teach a method wherein the expression of any of the genes in claims 2-5 are the basis for adjusting the normalized expression value of CD177, particularly not at least one gene selected from the following genes: GNLY, S100A9, C3AR1, ADGRE3, CX3CR1, IFIH1, OAS2, OAS3.
Demaret does not teach normalizing to a housekeeping gene.
Khatri et al. teach a similar assay to that of Hall, namely an assay for distinguishing between sepsis and SIRS. The reference teaches that C3AR1 expression is a biomarker of sepsis (p. 4, 1st full ¶ and throughout). Khatri et al. demonstrates a method for diagnosing sepsis wherein the values of different markers are adjusted relative to one another, for example by multiplying and dividing values of different markers, according to a model (see p. 5-6).
Khatri et al. further teach that gene expression can measured using microarrays or a variety of other methods including RT-PCR (p. 25 line 25 and following). The reference teaches RT-PCR can be normalized to housekeeping genes to minimize errors and the effects of sample-to-sample variation (p. 37, final ¶).
It would have been obvious to have modified the method taught by Demaret in view of Hall so as to have incorporated any one or all of the markers taught by Khatri into the method for diagnosis of sepsis taught by Demaret in view of Hall. One would have been motivated to do so in order to provide a more complete assessment of the sepsis status of the individual by including more informative markers. Furthermore, it would have been obvious to substitute the RT-PCR with normalization method taught by Khatri et al. for the microarray method taught by Demaret because both methods taught techniques for detecting gene expression markers and could be substituted for one another to achieve the predicable outcome of measuring a normalized expression from samples.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-11 and 13 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-11 and 13 of copending Application No. 18/014878 (reference application).
The reference claims anticipate the instant claims.
THESE REJECTIONS ARE MADE OVER THE COPENDING CLAIMS IN VIEW OF HALL AND KHARTI:
Claims 1-11 and 13 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 3-11 and 13 of copending Application No. 18/014934 (reference application).
Claims 1-11 and 13 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 3-11 and 13 of copending Application No. 18/014801 (reference application).
Claims 1-11 and 13 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 5-11 of copending Application No. 18/880056 (reference application).
Claims 1-11 and 13 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 5-11 of copending Application No. 18/880053 (reference application).
Each of these reference applications is taken in view of Hall and Kharti.
These copending applications methods for measuring phenotypes (complication, healthacare-associated infection infection, risk of death) by methods that employ the detection of the level of CD177 in combination with other genes. Regarding claims 6-11 and 13, these limitations are additionally taught in the copending claims
The claims do not teach the methods of amended claim 1, regarding the comparing and classifying steps.
Nonetheless, the teachigns of Hall and Kharti are fully incorporated here.
It would have been obvious to have modified the methods of the copending claims that recite detecting expression of CD177 so as to have included comparing and classifying steps in the assay for detecting the phenotype as the application of a known technique to achieve a predictable outcome of predicting a phenotype. Here it is noted that the instant claims do not state in the process steps what the “risk” being determined is for, and practicing any of the copending methods will result in classifying risk of a patient.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Remarks
Any rejection not reiterated, updated or specifically addressed was overcome by amendment to the claims 3/10/26.
The 101 rejection has been updated to address the amended claims. Applicant argues that the claims are not directed to a law of nature because healthcare-associated infection does not occur in nature. However, the correlation that people with increased CD177 are at greater risk of infection is a naturally occurring phenomenon occurs without any input from man. Therefore, it is considered a law of nature.
Furthermore, the amened claims additional recite abstract ideas as noted in the rejection.
Applicant states that the claim as a whole integrates the judicia exception by determining risk. However, “determining risk” is itself an abstract idea judicial exception. The argument is not persuasive. The claims do not apply or use the recited exceptions in any way.
Newly formulated art and double patenting rejections are set forth to address the amended claims.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. WO2020/002602 teaches that patients with sepsis are at high risk of nosocomial infections. This is further supported by Otto et al. (Critical Care 2011, 15:R183 http://ccforum.com/content/15/4/R183), see abstract and throughout.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Juliet Switzer whose telephone number is (571)272-0753. The examiner can normally be reached Monday to Thursday, 8:00 AM-3:30 PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Winston Shen can be reached at (571)-272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Juliet Switzer
Primary Examiner
Art Unit 1682
/JULIET C SWITZER/ Primary Examiner, Art Unit 1682
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