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 .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
DETAILED ACTION
Election/Restrictions
Applicant's election with traverse of Group I (diagnosing lung cancer using one of the four biomarkers listed) as well as the species of PGBD5, Cyfra21-1, blood, and ELISA in the reply filed on 4/3/26 is acknowledged. The traversal is on the ground(s) that there is no undue burden. This is not found persuasive because this is a mere assertion. Applicant does not support this conclusion with any rationale as to why there would be no undue burden nor does Applicant point to any deficiency in the Examiner’s articulation of the reasons there would be undue burden.
The requirement is still deemed proper and is therefore made FINAL.
After examination, the elected species of PGBD5 is allowable over the prior art. Per MPEP §803.02(III), the examination has been extended to another species. As there is a prior art rejection for CTSG, the other non-elected species remain withdrawn.
Claims 1-20 are pending.
Claims 6-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 4/3/26.
Claims 1-5 are under examination.
Drawings
The drawings are objected to because:
Figure 1 does not describe any difference between the darker circles and the lighter circles, nor is such a description/legend found in the specification.
Further, while some of the labels are attached to dots, other labels do not appear clearly associated with any particular dot. For example, CAT is nearby at least four dots where it could conceivably be referring to any one or more of them.
Several labels such as PSAP (PSAF?), ADGRL4 and SFTPB labels are obscured by other elements of the figure.
There is a sting of letters near the top center that is not legible. It is unclear what some of the letters are; the first label might be CACNA2F1, though this does not appear to correlate to any known protein. Further, it is unclear where one label ends and another begins, e.g., this could be two labels, three, or more.
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Figure 2 appears to use the same label for all of “tentative”, “confirmed”, and “rejected” in the legend. While it is clear there are differences in the shading in the graph, it is unclear what shade correlates to which label. Further, there appears to only be two shades used in the graph while there are three labels.
Further, as with figure 1, several of the labels in the graph are obscured by other elements and several labels are ambiguous as to which dot they are meant to label. For example, the GSN label might apply to any of the five dots around it and GSN or GPT might refer to the same dot between those labels.
Figure 3 contains non-English characters. 37 CFR 1.52(b)(1)(ii) requires the application to be in the English language.
Figure 6 is labels as “Figurc 6”
Further, the lefthand label is illegible as it is obscured by other elements of the figure.
The righthand figures are unnecessarily shaded. The shading does not appear to confer any information. See 37 CFR 1.84 (m) for guidance on appropriate uses of shading as well as the prohibition of using shading where it reduces legibility. See also 37 CFR (p)(3) which states that numbers should not be placed upon shading.
Figure 7 uses indistinguishable shades of grey for all of the labels. CEA and 3MP appear to be the same shade of black. The other three all appear to be the same shade of grey. It cannot be determined which line corresponds to which label.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
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 1-5 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon (correlation) without significantly more.
Step 1: It must first be determined if the claim is to a statutory category and, if so, proceed to step 2A prong 1. Claims 1-5 are a method and fall within the statutory category of a process.
Step 2A, prong 1: Prong 1 requires the Examiner to evaluate whether the claim recites a judicial exception and, if so, proceed to prong 2. In this case, the claims recite “classifying the individual as either a healthy individual or an individual with lung cancer based on the determined concentration of the biomarker”. The claim is directed to the judicial exception of observing naturally occurring biomarkers (the biomarker; PGBD5) and making mental conclusions (“classifying”) based on that observation.
Step 2A, prong 2: Prong 2 requires the Examiner to evaluate whether the claim recites additional elements that integrate the exception into a practical application of that exception and, if not, proceed to step 2B. In order to integrate the recited judicial exception into a practical application, the claim will apply, rely on, or use the judicial exception that imposes a meaningful limit such that the claim is more than a drafting effort to monopolize the judicial exception. Examiners evaluate integration by identifying additional elements in the claim beyond the judicial exception and evaluating those elements individually and in combination to determine whether they integrate the exception in to a practical application. Examples that have been found by the Courts in which the exception was not integrated into a practical application include:
Mere instructions to implement an abstract idea on a computer
Adding generic instructions that the judicial exception should be used ("apply it")
Adding insignificant extrasolution activity to the exception ("mere data gathering")
Generally linking the use of the exception to a particular technological environment or field of use
In this case, there are no steps occurring after the judicial exception and so there is no additional elements to integrate the exception. The “classifying” step is a mental conclusion that is also part of the judicial exception itself. To the extent that this is considered an additional step, “classifying” is recited at such a high level of generality that it amounts to no more than “apply it”. The other elements (providing; determining) occur prior to the judicial exception and are insignificant extrasolution activity, such as the “mere data gathering” steps found to be insufficient by the Courts.
Step 2B: Where a claim does not integrate the exception, a claim may nevertheless be patent eligible, for example where additional elements are “significantly more” than the exception such that the additional elements were unconventional in combination. Considerations include whether or not the claim adds a specific limitation or combination of limitations that are not well-understood, routine, conventional activity in the field, which is indicative that an inventive concept may be present; or simply appends well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, which is indicative that an inventive concept may not be present.
In this case, there are two steps other than the judicial exception itself: the providing step and the determining step. However, these are recited at such a high level of generality that they represent no more than routine, well-understood steps.
The determining step is the observation of the relevant biomarker in a “liquid sample” such as blood (claim 2). The Courts have explicitly recognized the generic observation of a biomarker in blood to be well-understood, routine, and conventional; see MPEP §2106.05(d)(II).
In order to determine/observe said biomarker, the sample must have been provided. Absent providing the sample, there is no test to be performed. If the Court has found that determining the level of a biomarker, detecting DNA, analyzing DNA, and amplifying nucleic acids are routine, then providing the samples necessary to perform those actions must also be routine.
In addition to the direct recognition by the Courts, the following are provided as evidence of the routine nature of providing a blood sample for biomarker detection:
US20190331679 (form 892): discloses obtaining a blood sample (claim 5) and detecting biomarkers (claim 1).
US20170254822 (form 892): discloses providing a bodily fluid sample and detecting a level of a biomarker (claim 1).
US20170219611 (form 892): discloses providing a bodily fluid sample and determining a concentration of a biomarker (claim 1).
US20150377905 (form 892): discloses obtaining a blood sample and measuring levels of biomarkers (claim 19).
Taken as a whole, the claim amount to no more than recognizing the relevance of a particular biomarker to a particular disease and seeks to monopolize the mere observation of that biomarker. Once informed of the relevance, the mental step of “classifying” is simply the result of that information and not a practical integration of the judicial exception.
Regarding claim 2, this claim limits the “liquid sample” to, e.g., blood. Detecting the biomarker in blood fails to provide patent eligibility for the reasons above.
Regarding claim 3, the blood sample being a “whole blood” sample does not differentiate the claim from “blood”. Detecting the biomarker in blood fails to provide patent eligibility for the reasons above.
Regarding claim 4, the Court has recognized the detection of a biomarker by “any means” is insufficient. Assays such as ELISA are one such means. However, even without the Courts’ guidance, the manner of detecting the biomarker falls into the category of data gathering (failing step 2A prong 2) and ELISA is a ubiquitous method of measuring proteins that has been conventional in the art for roughly 50 years. See for example:
US20190331679 paragraph 88-89 for descriptions of common immunoassays.
US20170254822 paragraph 130 for disclosure of ELISA.
US20170219611 paragraph 163 and table 1 for disclosure of ELISA.
US20150377905 paragraph 13 for disclosure of ELISA.
Regarding claim 5, the claim adds an additional biomarker to be observed. This element is part of the judicial exception itself (determining the biomarker in claims 1 and 5 and the relevance to lung cancer, resulting in “classifying”). Thus, claim 5 cannot provide an element “in addition to” the judicial exception.
Therefore, claims 1-5 are not patent eligible.
Claim Rejections - 35 USC § 112
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.
Claim 5 is 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 is directed to detecting “a biomarker” i.e., a single biomarker. Claim 5 states that “the biomarker” (the singular biomarker in claim 1) “further comprises” a wholly different protein.
In one interpretation, this is meant to require detecting more than one biomarker, e.g., the concentration of the biomarker in claim 1 and the concentration of the biomarker in claim 5.
In another interpretation, “the biomarker” is the concentration itself. In this interpretation, the concentration of the marker in claim 1 and the concentration of the marker in claim 5 is combined to generate a single concentration of “a biomarker”.
Therefore, claim 5 is indefinite.
Claims 1-5 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.
The claims use the term “healthy”. There is no specific definition of this phrase in the specification as filed. An ordinary definition of this term would require the subject not to have any diseases or disorders at all. For example, a subject with Alzheimer’s disease would not ordinarily be considered “healthy” even if that subject does not have lung cancer. This is supported by the specification such as at paragraphs 66 (“normal in a conventional physical examination”) or 82 (“normal healthy person”).
However, this interpretation is undermined by, e.g., paragraph 99. In paragraph 99 of the specification, a subject with lung cancer is confirmed by pathological examination, whereas a healthy subject is “normal in a physical examination” whether or not the subject had lung cancer.
Thus, it is also possible that the claim defines “healthy” vs “lung cancer” based on the test that is performed. A subject that has lung cancer may not be included in the “lung cancer” classification if they are normal in a physical examination, despite the claimed classification being “individual with lung cancer”.
This leads to several issues with the scope of the claim. The specification does not define what is required of a “physical examination”. Depending on the tests one chooses to include in this examination, two different people may find the same subject “normal” and “not normal”, leading to confusion of whether or not the subject is classified as “healthy”. Further, it is unclear what the scope of the claim covers when the same subject has both pathology (lung cancer) but is normal in a physical examination (healthy) or what occurs when a subject lacks lung cancer pathology (not lung cancer) but is also not normal in physical examination (not healthy).
Thus, while the claim requires classification of “healthy” vs “lung cancer” based on the concentration of one or two biomarkers, the specification makes it unclear if “based on” is meant to be the sole definition of these categories in contradiction to the specification or if there are other characteristics and, if so, what those are.
Therefore, claims 1-5 are indefinite.
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 1-5 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for diagnosing lung cancer vs healthy individuals when including the biomarkers in claim 5 and when testing the specific individuals in the instantly disclosed cohort in a blood sample, does not reasonably provide enablement for distinguishing lung cancer vs healthy subjects without those additional biomarkers, in samples other than blood, or in individuals/cohorts other than the ones instantly tested. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
There are many factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue. These factors include, but are not limited to: 1) nature of the invention, 2) breadth of claims, 3) amount of direction or guidance by the inventor, 4) relative skill of those in the art, 5) level of predictability in the art, 6) state of the prior art, 7) existence of working examples, and 8) quantity of the experimentation needed to make or use the invention. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)
The nature of the invention is diagnosing subjects with lung cancer vs those subjects which are healthy. There is no specific definition of “healthy” in the specification. Even in light of the specification, the scope of the claim is unclear. Nevertheless, this enablement rejection applies regardless of the definition, whether or not “healthy” means “not diseased” or “diseased but not lung cancer”.
The breadth of the claims is such that determining the concentration of a single biomarker, such as PGBD5, is sufficient to classify a subject as either having “lung cancer” or “healthy”. The guidance in the specification is that one group of subjects has increased PGBD5 while another does not. Paragraph 99 notes that those with increased PGBD5 are those who have lung cancer upon pathological examination. This paragraph also notes that “healthy” includes those who have lung cancer but are normal during a physical examination. The disclosed data combines those subjects who are actually healthy as well as those who have lung cancer. Based solely on the biomarker concentration, it is unclear what concentration distinguishes those individuals having lung cancer (which includes those normal during a physical examination) vs those who do not have lung cancer.
Further, the art recognizes that biomarkers such as PGBD5 are not differential for lung cancer. Stallard (form 892) states “nerve cells in healthy people have some of the highest levels of PGBD5 proteins of all tissues in the body”. Stallard also states that PGBD5, when abnormally activated, makes a protein (increases concentration of that protein) that leads to “many pediatric cancers”. Bathe (wo2021195787; form 892) teaches that the gene product (protein) level (concentration) of PGBD5 is indicative of thyroid cancer risk (claim 1). US 20200224282 (form 892) teaches PGBD5 is indicative of breast cancer subtypes (claim 18).
It is noted that the art cited does not appear to measure PGBD5 in a blood sample. However, this adds to the levels of experimentation necessary. Since it is established that PGBD5 in other samples fails to differentiate lung cancer, without evidence that PGBD5 blood/serum/plasma levels distinguish lung cancer vs other cancers it would require others to determine for themselves whether or not Applicant’s observations of blood levels are enabled to make the claimed classification. While it is possible that only those with lung cancer have increased blood levels of PGBD5, it is equally possible that other cancers have the same increase, similar to the increase noted by the art in other samples. Further, since it appears that Applicant includes individuals with lung cancer in the “healthy” category, it would similarly require undue experimentation for others to determine which levels indicate those “with lung cancer” that belong to the “individual with lung cancer group” when those levels are also indicative of being in the “healthy” category as even the working examples do not appear to make this distinction.
While the instant examples suggest that a cohort can be divided into “individual with cancer” or “healthy” based solely on a single biomarker, the art has tested this hypothesis and failed. See Human protein atlas CTSG (HPA-CTSG; form 892) which measured CTSG in healthy subjects, various cancers, as well as many other diseases in blood in 2356 samples across 32 cohorts. As seen from the table on the first page, CTSG is not significantly different in lung cancer, where lung cancer patients had nearly identical levels to those with ovarian cancer, prostate cancer, schizophrenia, psoriasis, and pregnancy. Thus, while it appears that not even the instant examples are sufficient to enable the instant claims, even if they are, they are specific to that particular cohort and does not generalize to the population at large.
In addition to the above, the instant specification only demonstrates the level in blood. It is unclear if the levels are even detectable in other liquid samples such as sweat, saliva, or urine. PGBD5 is an intracellular protein “physically associated with genomic…sequences” (Henssen 2017; form 892). While a blood sample contains red blood cells and a serum sample was in contact with those red blood cells, this is not typically the case for sweat, urine, or saliva. PGBD5 is not a normally secreted protein and so there is no evidence nor scientific rationale to expect the levels in plasma to be reflected in all liquid samples including, e.g., sweat. Malesu (form 892) teaches that changes in blood biomarkers do not always correlate to those same changes in sweat, thereby requiring others to test all liquid samples to determine for themselves whether or not the claimed classification can be made “based on” the claimed biomarkers.
When combined with other biomarkers that are differential for lung cancer, such as CYFRA21-1, the claims are enabled, but this is not commensurate with the claim scope.
Therefore, claims 1-5 are not enabled.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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) 1-3, 5 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hedrick (WO 2022040299; form 892) in view of Rastel (form 892).
Regarding claim 1, Hedrick teaches detecting the expression of CTSG protein (claims 2 and 3) in blood (claim 4) of a patient suspected of having lung cancer (claims 5 and 7) to detect ENePs (claim 1). These ENePs express elevated levels (concentration) of CTSG (claim 20) for diagnosing lung cancer (claims 15 and 19).
Hedrick therefore would have made obvious providing a liquid sample obtained from an individual (blood), determining the concentration of CTSG in the blood, and classifying (diagnosing) the individual as either healthy (does not have cancer) or having lung cancer (diagnosing the presence of lung cancer; indicated the presence of cancer). While Hedrick teaches alternatives, these are selected from a finite list. Blood is the single preferred sample (e.g., claim 16). There are eight biomarkers (claim 20) and six cancers (claim 19). This is less than 50 combinations and, importantly, there is no evidence in Hedrick or the art of record to suggest unpredictability of these alternative combinations.
Further, the enablement rejection above includes the instant combination of CTSG and lung cancer. The same issues would have existed with the disclosure of Hedrick. However, to the extent that the instant application might be enabled, so to would the prior art because both the instant application and prior art note the relationship between increased CTSG in blood and lung cancer.
Additionally, Rastel teaches CYFRA 21-1 “is a sensitive tumor marker for NSCLC, especially squamous cell lung cancer” in serum (abstract). As the purpose of Hedrick was to diagnose cancers, including specifically lung cancer, it would have been obvious to combine this with other known biomarkers. The combination of CTSG and CYFRA 21-1 would have predictably allowed the ordinary artisan to diagnose lung cancer in blood, classifying the subjects into “having lung cancer” or healthy.
Regarding claim 2, Hedrick teaches the sample is blood (claim 16). Rastel teaches the sample is serum.
Regarding claim 3, Hedrick teaches peripheral blood samples (paragraph 35). Without disclosure of any particular processing of the blood samples, this would have made it obvious that the samples were whole blood samples. Rastel teaches the sample is serum.
Regarding claim 5, Rastel teaches Cyfra21-1 is specific for lung cancer as described above and would have been obvious to include for the reasons above.
Therefore, claims 1-3 and 5 would have been obvious.
Claim(s) 4 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hedrick (WO 2022040299) in view of Rastel as applied to claims 1-3 and 5 above, and further in view of Slamon (US20190292605; form 892).
Regarding claim 4, Hedrick teaches measuring the protein but does not disclose any particular methodology for doing so. Rastel teaches immunoradiometric sandwich assays, which differ from assays such as ELISA by using a radiolabel as the reporter rather than an enzyme.
Slamon also teaches measuring protein biomarkers to test lung cancer samples (claims 38 and 49). Slamon teaches ELISA is appropriate for this task (claim 47). It would have been obvious to use a known method of detecting protein concentrations when set to detect protein concentrations. It would have been obvious to use the known methods of Slamon (ELISA) when measuring other biomarkers, such as those in Hedrick and Rastel.
Therefore, claims 1-5 would have been obvious.
Allowable Subject Matter
There is no prior art rejection of Applicant’s elected species of PGBD5. As noted above, no other art of record detected PGBD5 in blood even when attempting to do so. As such, there was no reasonable expectation that PGBD5 in blood could act as a biomarker for anything, much less specifically for lung cancer.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ADAM M WEIDNER whose telephone number is (571)272-3045. The examiner can normally be reached M-T 9-18; W-R 9-15.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Stucker can be reached at 571-272-0911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Adam Weidner/ Primary Examiner, Art Unit 1675
Prosecution Insights