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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 11/10/2025 has been entered.
Claims 1, 5, 14, 16, 18, 20, 40, 47 and 73 are amended. Claims 1, 5, 12, 14, 16-20, 40-43, 47 and 71-73 are under examination.
Specification
The disclosure is objected to because of the following informalities. Table 5 of the instant specification has shading that makes many of the correlation coefficients invisible. While paragraph [00262] states that the shading is used to show the extent of positive/negative correlation, the specification should not contain shading. The specification must have text written plainly and legibly in portrait orientation and presented in a form having sufficient clarity and contrast between the paper and the writing thereon to permit the direct reproduction of readily legible copies in any number by use of photographic, electrostatic, photo-offset, and microfilming processes and electronic capture by use of digital imaging and optical character recognition; and only a single column of text. See 37 CFR 1.52(a) and (b).
Appropriate correction is required.
Claim Interpretation
The clause “determining, in one or more test ex vivo lung perfusion (EVLP) perfusate samples of a donor lung, one or more parameter values related to a level of polypeptide of biomarkers IL-6, IL-10 and IL-1β, optionally in combination with one or both of sTNFR1 and sTREM1” in claims 1 and 47 is interpreted as reading upon determining the parameter values related to the levels of:
IL-6, IL-10 and IL-1β;
IL-6, IL-10, IL-1β and sTNFR1;
IL-6, IL-10, IL-1β and sTREM1; or
IL-6, IL-10, IL-1β, sTNFR1 and sTREM1.
In addition, the phrase “optionally determining in one or more test EVLP perfusate samples of the donor lung, one or more biochemical parameter values and/or determining one or more physiological parameter values of the donor lung” in claims 1, 5 and 14 is interpreted as, in addition to the above, determining in the test EVLP donor lung perfusate samples:
Biochemical parameter values;
Physiological parameter values;
Both biochemical and physiological parameter values; or
Neither biochemical and physiological parameter values.
In these clauses, there is no ambiguity as to which alternatives are covered by the claim. See MPEP 2173.05(h)(II).
Claim 1 is interpreted as requiring the following:
A method for the screening, diagnosing, or detecting of outcome/risk as it relates to donor lungs, comprising:
determining, in one or more test ex vivo lung perfusion (EVLP) perfusate samples of a donor lung, one or more parameter values related to a level of polypeptide biomarkers IL-6, IL-10 and IL-1β;
comparing the one or more parameter values related to a level of each of the biomarkers in the one or more perfusate samples with control EVLP data or a cut-off level, wherein the differential level is indicative of outcome/risk; and/or
using the one or more parameter values related to a level of the biomarkers in combination as part of an algebraic calculation or model of outcome/risk, and
selecting said donor lung for transplant when the outcome/risk is acceptable or below the cut-off value, preparing said donor lung for transplant and/or transplanting said donor lung into a suitable recipient, or discarding the donor lung, subjecting the donor lung to further EVLP and subsequently reassessing the donor lung outcome/risk when the donor lung has an outcome/risk below a selected threshold and/or using the donor lung for research or other purposes when the outcome/risk is unacceptable or above the cut-off value.
Everything else in the claim is optional.
Claim 5 depends from claim 1 and recites predicting a patient outcome (PO) variable for a lung transplant recipient after transplant in the preamble followed by the required steps of obtaining test EVLP perfusate sample(s) and determining one or more parameter values related to a polypeptide level of biomarkers IL-6, IL-10 and IL-1β and comparing one or more parameter values for the donor lung with control EVLP data or a cut-off level. All of the steps related to the PO variable and PO variable score are optional.
Claim 14 depends from claim 1 and is interpreted as early detection of donor lungs that will be declined at the end of the EVLP process followed by the required steps of obtaining EVLP perfusate sample(s) and determining one or more parameter values related to a polypeptide level of biomarkers IL-6, IL-10 and IL-1β, comparing one or more parameter values for the donor lung with control EVLP data or a cut-off level, continuing perfusion if the parameter value(s) indicates the donor lung is suitable for transplantation and discontinuing perfusion if the parameter value(s) indicates the donor lung will be declined. The last step is interpreted as a choice between two options based on parameter value(s) outcome. All other steps are optional.
Claim 16 depends from claim 1 and is interpreted as selecting a candidate donor lung for transplant followed by the required steps of obtaining EVLP perfusate sample(s) and determining one or more parameter values related to a polypeptide level of biomarkers IL-6, IL-10 and IL-1β, comparing one or more parameter values for the donor lung with control EVLP data or a cut-off level, and selecting the donor lung for transplant according to the one or more parameter values. The step reciting generating a transplant suitability score is optional.
Claim 47 is interpreted as requiring the following:
A computer-implemented method for detecting outcome/risk as it relates to donor lungs, comprising:
obtaining ex vivo lung perfusion (EVLP) data relating to one or more test EVLP perfusate samples of a donor lung, the EVLP data comprising one or more parameter values relating to a level of polypeptide biomarkers IL-6, IL-10 and IL-1β,
querying, via one or more computers, a database of control EVLP data or a cut-off level associated with patient outcome or transplant suitability to compare the EVLP data to the control EVLP data or cut-off level; and
determining a ranking score based on the comparison between the EVLP data and the control EVLP data or cut-off level,
selecting said donor lung for transplant when the outcome/risk is acceptable or below the cut-off value, preparing said donor lung for transplant and/or transplanting said donor lung into a suitable recipient, or discard the donor lung, subjecting the donor lung to further EVLP and subsequently reassessing the donor lung outcome risk, and/or using the donor lung for research or other purposes when the outcome/risk is unacceptable or above the cut-off value.
Everything else in the claim, including the steps set forth after the “selecting” step are optional.
Objections/Rejections Withdrawn
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Rejections - 35 USC § 112(b)
The rejection of claims 1, 5, 12, 14, 16-20, 40-43, 47 and 71-73 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 as set forth at pages 5-7 of the Office action mailed 07/08/2025 is withdrawn in response to Applicant’s amendment. First, the claims have been amended to recite acceptable alternative listings. Second, claim 18 has been amended to delete “at least”.
Claim Rejections - 35 USC § 103
The following rejections under 35 U.S.C. 103 are withdrawn in response to Applicant’s amendment of independent claims 1 and 47 to require determining one or more parameter values related to a level of the polypeptide biomarkers IL-6, IL-10 and IL-1β. The applied prior art references suggest IL-6, IL-8 and IL-1β as a panel of biomarkers, but not IL-10.
The rejection of claims 1, 5, 12, 14, 16-20, 40, 42, 43, 71 and 72 as being unpatentable over Keshavjee et al. (US 2015/0377904—on IDS filed 02/21/2024) in view of Nakajima et al. (J Heart Lung Transplant 2017; 36: 577-585—on IDS filed 01/10/2022).
The rejection of claim 47 under 35 U.S.C. 103 as being unpatentable over Keshavjee et al. (US 2015/0377904 —on IDS filed 02/21/2024) in view of Nakajima et al. (J Heart Lung Transplant 2017; 36: 577-585 —on IDS filed 01/10/2022) and Cohen (WO2016094330).
The rejection of claim 73 under 35 U.S.C. 103 as being unpatentable over Keshavjee et al. (US 2015/0377904—on IDS filed 02/21/2024) and Nakajima et al. (J Heart Lung Transplant 2017; 36: 577-585—on IDS filed 01/10/2022) as applied to claims 1, 5, 12, 14, 16-20, 40, 42, 43, 71 and 72 above, and further in view of Iskender et al. (J Heart Lung Transplant, February 2018; 37:283-291) is withdrawn because (1) the aforementioned rejection upon which it is based is withdrawn and (2) the applied prior art does not teach or suggest determining one or both of sTNFR1 and sTREM1. To clarify, claim 73 is interpreted as requiring the measurement of IL-6, IL-10 and IL-1β AND either (1) sTNFR1 and sTREM1 OR (2) sTNFR1 or sTREM1. The measurement of sTNFR1 and/or sTREM1 is optional in claim 1, but not in claim 73.
Further, Applicant argues persuasively at p. 13, 4th paragraph of Applicant’s Remarks filed 11/10/2025 that Iskender et al. teach that IL-10 is an anti-inflammatory cytokine and cautions that their non-specific filtering method has the “unwanted effect” of removing anti-inflammatory cytokines from circulation, including IL-10 (see p. 290, left column, 1st paragraph). Given this warning by Iskender and colleagues, one having ordinary skill in the art would not be motivated to include IL-10 in a screening panel of pro-inflammatory biomarkers.
Finally, regarding the arguments at p. 13, 2nd and 3rd paragraphs, it is noted that the claims use “comprising” language, and are therefore not limited to the inclusion of other elements, such as the inclusion of additional cytokines in a risk panel. Further, the claims explicitly recite the differential IL-1β, IL-6 and IL-10 levels are indicative of outcome/risk optionally after transplant; that is, the differential cytokine levels may also be used to determine outcome/risk prior to transplant.
Double Patenting
The following rejections on the ground of nonstatutory double patenting are withdrawn in response to Applicant’s amendment of the claims to include IL-10. As noted in the preceding section regarding the withdrawn rejections under 35 USC 103, it would not be obvious to include IL-10 in a panel of donor lung EVLP biomarkers.
The provisional rejection of claims 1, 5, 12, 14, 16-20, 40-43, 47, 71 and 72 as being unpatentable over claims 1, 2, 7, 8, 10, 13, 16 and 18 of copending Application No. 18/694,171 in view of Nakajima et al., Andreasson et al. and Cohen.
The rejection of claims 1, 5, 12, 14, 16-20, 23, 28, 40, 42, 43, 47, 71 and 72 as being unpatentable over claims 1-13 of U.S. Patent No. 9,835,630 in view of Nakajima et al., Andreasson et al. and Cohen.
New Objection/Rejections/Maintained Rejections
Claim Objections
Claims 1, 5, 47, 71 and 72 are objected to because of the following informalities.
(i) Claim 1, lines 4-5 recites “a level of polypeptide of biomarkers IL-6, IL-10 and IL-1β”, however, the “of” preceding “biomarkers” is unnecessary. In the clause beginning “comparing the one or more parameter values…”, claim 1 recites “of each the biomarkers”, but presumably “of each of the biomarkers” was intended. In the clause beginning “using the one or more parameter values…”, claim 1 recites “more or more”, but presumably “one or more” was intended. The “or” in the penultimate line in claim 1 should be deleted: “when the outcome/risk
The optional clauses of claim 5 recite both “PO variable score” and “PO score”. For the sake of parallel construction and consistency, use a single phrase. In addition, claim 5 depends from claim 1, and “PO” was already defined as “patient outcome” in claim 1, thus it is not necessary to redefine in claim 5. Claim 71 also has this issue.
In claim 47, line 2, there should be a comma (,) after “donor lungs”. Further, “the method” is not necessary (for comparison, see claim 1, line 2). In addition, lines 4-5 recite “a level of polypeptide of biomarkers IL-6, IL-10 and IL-1β”, however, the “of” preceding “biomarkers” is unnecessary. The “or” at the end of the “selecting” clause in claim 47 should be deleted: “when the outcome/risk
In claim 72, which depends from claim 1, “ICU” does not need to be defined because it was already defined in claim 1 as “intensive care unit”.
Appropriate correction is required.
New Rejections
Claim Rejections - 35 USC § 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.
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, 5, 12, 14, 16-20, 40-43, 47 and 71-73 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.
Claims 1 and 47 recite “the biochemical data optionally comprising at least one of: base excess, bicarbonate, potassium, sodium, calcium, chloride, glucose, lactate and pH, and the physiological data optionally comprising at least one of: driving pressure, PCO2 (measured and differential), PO2 (measured and differential), airway pressure, static and dynamic compliance, PA and/or LA pressure, and pulmonary vascular resistance”. The recitation of “optionally comprising at least one of” preceding a list of potential biochemical and physiological data measurement alternatives gives rise to ambiguity as to what is meant to be included in each of these lists of alternatives.
The clause beginning “selecting said donor lung for transplant” in claims 1 and 47 recite the alternatives:
Discarding the donor lung;
Subjecting the donor lung to further EVLP and subsequently reassessing the donor lung outcome/risk when the donor lung has an outcome/risk below a selected threshold; and/or
Using the donor lung for research or other purposes when the outcome /risk is unacceptable or above the cut-off value.
The use of “and/or” in this context is indefinite because the three alternatives are mutually exclusive. Specifically, the lung cannot be both discarded (i) and (ii) subjected to further reassessment or (iii) used for research. Further, the donor lung cannot have both an outcome/risk below (ii) and above a cut-off value (iii). Claims 12 and 14, which recite the alternatives (i) and (iii), also have this issue.
Claim 5 recites the PO variable is selected from ICU length of stay, post-transplant hospital length of stay, number of days on a ventilator, APACHE score and post graft dysfunction (PGD) grade, optionally PGD/0/1 or PGD3. In the context of this clause, “optionally” is interpreted as exemplary language, similar to “for example” or “such as”. Exemplary language renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. It is not clear whether a PGD grade of 0/1 or 3 is an intended PO variable. See MPEP § 2173.05(d).
Claim 18 recites a number of distinct alternatives after which EVLP perfusate samples are collected separated by “and/or”, namely “after or at about 45 min of EVLP…and/or after or at about 4 hours”. The use of “and/or” in this context is indefinite because the alternatives are mutually exclusive. In addition, the clause following the list reciting “optionally between 1 hour and 4 hours…or between 1 hour and 2 hours of EVLP” is interpreted as exemplary language, similar to “for example” or “such as”. Exemplary language renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. It is not clear whether the alternative ranges following the list of times when EVLP perfusate samples are collected are intended limitations. See MPEP § 2173.05(d). The claim leads to confusion as to when the EVLP perfusate is collected.
Claim 20 recites the one or more parameter values comprises a concentration of the biomarkers, a rate of biomarker production of the biomarkers and/or a ratio of the concentration of each of the biomarkers in each combination, optionally wherein the ratio is the concentration of a subsequent perfusate sample concentration of an earlier perfusate sample. First, the phrase “in each combination” is confusing since claim 1, from which claim 20 depends, no longer recites a list of alternative biomarker combinations. Second, in the context of the claim, the “optionally” clause is interpreted as exemplary language, similar to “for example” or “such as”. Exemplary language renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. It is not clear whether the ratio is a concentration of subsequent to earlier perfusate sample. See MPEP § 2173.05(d). Finally, the of in the phrase “wherein the ratio is the concentration of a subsequent perfusate sample concentration of an earlier perfusate sample” is confusing. It is not clear whether a ratio of the concentration of subsequent perfusate to an earlier perfusate sample was intended.
The phrases in lines 5 and 8 of claim 40 recite “optionally between 1 hour and 3 hours or between 1.5 hours and 2.5 hours of perfusion”. In the context of the claims, these clauses, which follow a range of about 1 hour to about 4 hours is interpreted as exemplary language, similar to “for example” or “such as”. Exemplary language renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. It is not clear whether the “optionally” clauses set forth limitations or are merely illustrative. See MPEP § 2173.05(d).
Claims 5, 12, 14, 16-20, 40-43 and 71-73 are also rejected for depending from an indefinite claim without resolving the indefiniteness.
Claim Rejections - 35 USC § 112(a)
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.
Enablement
Claims 1, 5, 12, 14, 16-20, 40-43, 47 and 71-73 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 enablement requirement. The claims contain 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.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.” (See In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 Fed. Cir. 1988). These factors include, but are not limited to: (a) the breadth of the claims; (b) the nature of the invention; (c) the state of the prior art; (d) the level of one of ordinary skill; (e) the level of predictability in the art; (f) the amount of direction provided by the inventor; (g) the existence of working examples; and (h) the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The claims recite methods of screening, diagnosing or detecting outcome/risk in donor lungs comprising determining in ex vivo lung perfusion (EVLP) perfusate samples “one or more parameter values related to a level” of the biomarkers IL-6, IL-10 and IL-1β, wherein the donor lung is selected for transplant when the outcome risk is acceptable or below the cut-off value, or discarded when the outcome risk is unacceptable or above the cut-off value. The instant specification defines “parameter values related to a level” at paragraph [0064]:
The term “parameter value related to a level” or “level” as used herein interchangeably in relation to a biomarker refer to an amount (e.g. relative amount or concentration as well as parameter values calculable based thereon such as a rate or ratio) of biomarker (i.e. polypeptide related level) that is detectable, measurable or quantifiable in a test biological sample and/or a reference biological sample, for example, a test perfusate
sample and/or a reference perfusate sample. For example, the parameter value related to a level can be a rate such as pg/mL/hour, a concentration such as µg/L, ng/ml or pg/ml, a relative amount or ratio such as 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 10, 15, 20, 25, and/or 30 times more or less than a control biomarker or reference profile level. The control biomarker polypeptide level can, for example, be the average or median level in a plurality of known outcome lungs. Parameter values related to a level include concentration, rate of production and a ratio or fold increase (e.g. concentration at a later time point (such as 4 hours) divided by a concentration at an earlier time point for the same biomarker). The parameter values are EVLP data, for example from a test perfusate, and can also include the time after starting EVLP the perfusate sample was taken.
Thus, according to the instant specification, the recited parameter value includes concentration, rate of production and a ratio or fold increase and the concentrations, rates and ratios can be more or less than control, although the claim language suggests that lower than a cut-off value indicates a good outcome and that a higher than cut-off value indicates a poor outcome with respect to transplant, respectively.
The instant specification discloses that two scoring metric versions (v1 and v2) were calculated; v1 was “the product of the logarithmic concentration of IL-6 and IL-8” and v2 was “the product of the logarithmic concentration of IL-6, IL-8, IL-10 and IL1β” (see paragraph [00245]). The results shown in Fig. 1A are the relationship between concentrations of IL-6 and IL-8 (v1) and transplanted vs. declined lungs, in which the raw score value for transplanted lungs appears to be lower than that of the declined lungs (see Fig. 1A and paragraph [00247]). Similarly, Fig. 2A shows what appears to be a more pronounced relationship between concentrations of the combination of biomarkers IL-6, IL-8, IL-10 and IL-1β and transplanted vs. declined lungs, in which the raw score value for the transplanted lungs appears lower than that of the declined lungs (see Fig. 2A and paragraph [00247]). The specification discloses a lower raw score value of the biomarkers IL-6 and IL-8 (v1) and IL-6, CXCL8, IL-10, IL-1β, sTNFR1 and sTREM1 in the group of patients having a less than 3-day length of stay in the intensive care unit (ICU) compared to those with a greater than 3-day length of stay (see Figures 3A and 4A and paragraph [00249]). The data depicted in the Figures appear to show that the score values are lower in the lungs selected for transplantation (Figures 1-2) and lower in the lungs of patients who spent less than 3 days in the ICU (Figures 3-4).
The specification shows “a comparison of transplanted and declined lungs when scored using IL-6, CXCL8, IL-10, IL-1β, sTNFR1, sTREM1”, though it is not clear there is a difference between the two groups (see Fig. 5A, paragraphs [0033] and [00255]). Indeed, none of the Figures 1-5 are indicated as having significant differences between the groups tested. The specification discloses “[a] base model was built using physiological/biochemical parameters” [and the] biomarker data was added to the model to assess for significant improvement” and the model score is depicted as being significantly lower in the declined lungs than in the transplanted lungs (see Figures 6A and 6C; paragraph [00269]). While the claim language suggests a lower than cut-off value score indicates the donor lung is suitable for transplant, the data presented in the Figures is inconsistent, with score values being lower for some good outcomes, but not for others. Further, the evidence in the instant specification is not commensurate in scope with the breadth of parameter values related to a level of the biomarkers, a term which encompasses concentration, rate of biomarker production and ratios of concentrations. For example, the specification does not disclose what “ratio of the concentration of each of the biomarkers in each combination” correlates with what outcome.
Due to the large quantity of experimentation necessary to determine how to use the parameter values related to a level of IL-6, IL-10 and IL-1β to screen, diagnose or detect outcome risk in donor lungs, the lack of direction/guidance presented in the specification regarding whether the concentrations and rates of biomarker production are up- or down-regulated or what ratios of biomarkers can be used in the methods, the lack of guidance in the specification regarding rates of biomarker production and ratios and donor lung outcome/risk, the complex nature of the invention, the contradictory data disclosed in the specification, with both lower and higher score values correlating with good (and poor) donor lung outcomes, and the breadth of the claims which fail to recite limitations parameter values related to a level of the recited biomarkers, undue experimentation would be required of the skilled artisan to make and/or use the claimed invention.
Written Description
Claims 1, 5, 12, 14, 16-20, 40-43, 47 and 71-73 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 claims contain 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 written description rejection.
The claims recite methods of screening, diagnosing or detecting outcome/risk in donor lungs comprising determining in EVLP perfusate samples “one or more parameter values related to a level” of the biomarkers IL-6, IL-10 and IL-1β, wherein the donor lung is selected for transplant when the outcome risk is acceptable or below the cut-off value, or discarded when the outcome risk is unacceptable or above the cut-off value. The instant specification defines “parameter values related to a level” at paragraph [0064]. According to the instant specification, the recited parameter value includes concentration, rate of production and a ratio or fold increase and the concentrations, rates and ratios can be more or less than control.
The MPEP instructs that for inventions in emerging and unpredictable technologies, or for inventions characterized by factors not reasonably predictable which are known to one of ordinary skill in the art, more evidence is required to show possession (see MPEP 2163(II)(A)(3)(a)(i)). In deciding whether the application complies with the written description requirement of 35 USC 112(a) or 35 USC 112 (pre-AIA ), first paragraph, it is necessary to understand what Applicant has described and what Applicant is claiming. The instant specification discloses that two scoring metric versions (v1 and v2) were calculated; v1 was “the product of the logarithmic concentration of IL-6 and IL-8” and v2 was “the product of the logarithmic concentration of IL-6, IL-8, IL-10 and IL1β” (see paragraph [00245]). The relationship between concentrations of IL-6 and IL-8 (v1) and transplanted vs. declined lungs and between concentrations of the combination of biomarkers IL-6, IL-8, IL-10 and IL-1β and transplanted vs. declined lungs shows what appears to be lower raw score values for the transplanted lungs than that of the declined lungs (see Figures 1A and 2A; paragraph [00247]). Similarly, the specification discloses a lower raw score value of the biomarkers IL-6 and IL-8 (v1) and IL-6, CXCL8, IL-10, IL-1β, sTNFR1 and sTREM1 in the group of patients having a less than 3-day length of stay in the intensive care unit (ICU) compared to those with a greater than 3-day length of stay (see Figures 3A and 4A and paragraph [00249]). In summary, the data depicted in Figures 1-4 appear to show that the score values are lower in the lungs selected for transplantation (Figures 1-2) and lower in the lungs of patients who spent less than 3 days in the ICU (Figures 3-4).
The specification also shows “a comparison of transplanted and declined lungs when scored using IL-6, CXCL8, IL-10, IL-1β, sTNFR1, sTREM1”, though it is not clear there is a difference between the two groups (see Fig. 5A, paragraphs [0033] and [00255]). Indeed, none of the Figures 1-5 are indicated as having significant differences between the groups tested. The specification discloses “[a] base model was built using physiological/biochemical parameters” [and the] biomarker data was added to the model to assess for significant improvement” and the model score is depicted as being significantly lower in the declined lungs than in the transplanted lungs (see Figures 6A and 6C; paragraph [00269]). Thus, while the claim language suggests a lower than cut-off value score indicates the donor lung is suitable for transplant, the data presented in the Figures is inconsistent, with score values being lower for some good outcomes, but not for others. Further, the specification does not disclose what “ratio of the concentration of each of the biomarkers in each combination” correlates with what outcome. In this case, the specification does not disclose how to arrive at the scores for screening diagnosing or detecting outcome/risk of donor lungs using the concentrations, rates of biomarker production or what ratios can be used to carry out the claimed methods. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed methods.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116). The skilled artisan cannot envision the methods for determining the parameter values in order to screen diagnose or detect outcome/risk of donor lungs, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
Maintained Rejections
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.
The rejection of claims 1, 5, 12, 14, 16-20, 40-43, 47 and 71-73 under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more is maintained for reasons of record and the following. Independent claims 1 and 47 are amended to replace “when” for “if” in the “selecting” step, however, in this context, “when” is also conditional. See for instance, dependent claims 12 and 14, which are also conditional. As noted previously, claims 1, 5, 12, 14, 16-20, 40-43, 47 and 71-73 are drawn to the statutory category of a process (see Step 1 of the Revised Guidelines).
The first step in determining whether a claim recites patent eligible subject matter is to consider whether the claims recite an abstract idea, law of nature or a natural phenomenon (see Prong One of Step 2A in the Revised Guidelines). See the section above entitled “Claim Interpretation” for a summary of the broadest reasonable interpretation of independent claims 1 and 47, hereby incorporated. The judicial exceptions recited in claim 1 are the (1) comparing step and/or using the parameter values in combination as part of an algebraic calculation/model outcome risk, (2) the selecting step and the (3) subsequent reassessing step. The judicial exceptions recited in claim 47 are the (1) querying step, (2) the determining a ranking score based upon comparison step, (3) the selecting step and the (4) reassessing step. The judicial exceptions of comparing, algebraic calculation, reassessing, querying, determining and selecting describe the relationship between parameters related to IL-6, IL-10, and IL-1β levels and donor lung outcome/risk, optionally after transplant, but also prior to transplant, for instance, if the donor lung is deemed unacceptable and is discarded or used in research. The mental step of comparing biomarker levels in EVLP perfusate with a control or cutoff is similar to comparing information regarding a sample or test subject to a control or target data (see Univ. of Utah Research Found, v. Ambry Genetics Corp., 113 USPQ2d 1241 (Fed. Cir. 2014), or diagnosing an abnormal condition by performing clinical tests and thinking about the results (see In re Grams, 12 USPQ2d 1824 (Fed. Cir. 1989). The answer to Prong One of Step 2A is yes.
The second step in determining patent-eligibility of claimed subject matter is to consider whether the claims recite additional elements that integrate the judicial exception into a practical application (see Prong Two of Step 2A in the Revised Guidelines). Claim 1 and its dependents recite determining biomarker levels in EVLP perfusate samples, thus strongly implying that samples are obtained and an assay is carried out. Indeed, dependent claims 5, 14, 16 and 17 refer to obtaining samples and claim 42 recites that the biomarkers are detected using an immunoassay. Claim 12 recites the conditions under which the donor lung is selected or discarded and claim 14 recites the conditions under which perfusion is continued or discontinued. Claim 16 recites selecting a donor lung for transplant according to the results of the comparison of parameter values. Claims 18 and 19 recite the timing of the collection of the perfusate samples. Claims 40 and 73 recite the biomarkers determined. Claim 43 recites the further determination of biochemical and/or physiological parameter values and using one or both in combination with the parameter values “as part of an algebraic calculation or model of outcome/risk”, which is itself part of the judicial exceptions (see above). Claims 71 and 72 define the possible patient outcomes being diagnosed by the claimed methods. The dependent claims do not integrate the exceptions into a practical application because they are either part of the judicial exception (comparing cutoff values and algebraic calculations) or recite sample collection and detection of biomarkers via immunoassay, which are merely the necessary data gathering steps required in order to perform the mental analysis of comparison and diagnosis.
Claim 47 recites “obtaining EVLP data relating to one or more test EVLP perfusate samples of a donor lung”, and therefore does not require the active steps of collecting samples or carrying out immunoassays. Rather, the EVLP data may be read off of a chart and then fed into a computer to query a database of control EVLP data associated with patient outcomes. Although claim 47 recites the use of a computer to make the comparison and diagnosis, it is still drawn to a mental process. The MPEP 2106.04(a)(2)(III)(B) instructs that if a claim recites a limitation that can practically be performed in the human mind, with or without the use of a physical aid such as pen and paper, the limitation falls within the mental processes grouping, citing Synopsys, 839 F.3d at 1139, 120 USPQ2d at 1474 (holding that claims to the mental process of “translating a functional description of a logic circuit into a hardware component description of the logic circuit" are directed to an abstract idea, because the claims “read on an individual performing the claimed steps mentally or with pencil and paper”):
The use of a physical aid (e.g., pencil and paper or a slide rule) to help perform a mental step (e.g., a mathematical calculation) does not negate the mental nature of the limitation, but simply accounts for variations in memory capacity from one person to another. For instance, in CyberSource, the court determined that the step of "constructing a map of credit card numbers" was a limitation that was able to be performed "by writing down a list of credit card transactions made from a particular IP address." In making this determination, the court looked to the specification, which explained that the claimed map was nothing more than a listing of several (e.g., four) credit card transactions. The court concluded that this step was able to be performed mentally with a pen and paper, and therefore, it qualified as a mental process. 654 F.3d at 1372-73, 99 USPQ2d at 1695. See also Flook, 437 U.S. at 586, 198 USPQ at 196 (claimed "computations can be made by pencil and paper calculations"); University of Florida Research Foundation, Inc. v. General Electric Co., 916 F.3d 1363, 1367, 129 USPQ2d 1409, 1411-12 (Fed. Cir. 2019) (relying on specification’s description of the claimed analysis and manipulation of data as being performed mentally "‘using pen and paper methodologies, such as flowsheets and patient charts’"); Symantec, 838 F.3d at 1318, 120 USPQ2d at 1360 (although claimed as computer-implemented, steps of screening messages can be "performed by a human, mentally or with pen and paper").
Moreover, MPEP 2106.04(a)(2)(III)(C) instructs that performing a mental process on a generic computer is still drawn to a judicial exception. This is evident from claim 1 and its dependents that encompass collecting data and comparing the results.
The claims also recite a large number of optional embodiments, including, among others:
determining one or both of sTNFR1 and sTREM1;
determining one or more biochemical and/or physiological parameter values of the donor lung;
using the one or more parameter values in combination with the more or more biochemical and/or physiological parameter value(s) as part of an algebraic calculation or model of outcome/risk optionally after transplant, e.g., a negative post-lung transplant patient outcome or discontinuing EVLP;
using an artificial intelligence or a machine learning technique, e.g., a neural network to generate multiple classifiers/scores based on the multiple features, wherein each of the multiple classifiers/scores indicates one of multiple outcomes, the generating multiple classifiers/scores optionally comprising generating the multiple classifiers using the artificial intelligence technique or the machine learning technique.
However, as these are all optional, the claims all encompass embodiments in which they are not carried out. In summary, the judicial exceptions are not integrated into a practical application and the answer to Prong Two of Step 2A is no.
The final step in determining whether claims recite patent eligible subject matter is to consider whether they recite additional elements that amount to significantly more than the judicial exception. The claims do not recite any particular assay or steps that amount to significantly more than the judicial exception. The claims and specification list a number of well-known assays, for instance an ELISA (see paragraph [0060]):
A biomarker specific detection agent can include probes and the like as well as binding polypeptides such as antibodies which can for example be used with immunohistochemistry (IHC), Luminex® based assays, ELISA, immunofluorescence, radioimmunoassay, dot blotting, FACS, protein microarray, Western blots, immunoprecipitation followed by SDS-PAGE immunocytochemistry, other immunoassays and platforms (e.g., Simple Plex assay (Protein Simple)) as well as others. Mass spectrometry methods can also be used to detect one or more parameter values related to a level of a biomarker described herein.
In addition, Nakajima et al. (J Heart Lung Transplant 2017; 36: 577-585—on IDS filed 01/10/2022) teach the collection of perfusate samples during EVLP and using an ELISA (immunoassay) to measure IL-6 and IL-1β levels (see abstract; 578, right column, 3rd paragraph; p. 579, right column, 1st paragraph and p. 580, Figure 2). The additional steps are simply appending well-understood, routine conventional activities previously known to the industry, specified at a high level of generality to the judicial exception (see MPEP 2106.05(d)). Thus, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception.
Response to Arguments
Applicant argues at p. 12 of the Remarks filed 11/10/2025 that the amendment of claims 1 and 47 to replace “if” with “when” overcomes the rejection under 35 USC 101.
This argument has been fully considered, but is not found persuasive. The claim remains conditional because they do not affirmatively require any treatment. The “selecting” step recites the mental processes of selecting a donor lung for transplant when the risk is below a cutoff value and reassessing the donor lung risk when the risk is below a cutoff value or above a cutoff value. First, the donor lung is prepared and transplanted only when the risk is deemed acceptable or below a cutoff value, and therefore the steps of preparation and transplantation are conditional. Similarly, the donor lung is used for research or other purposes when the outcome/risk is above a cutoff value. The conditionality of the claims is also evidence by dependent claims 12 and 14. Second, one of the treatments includes discarding the donor lung, reassessing the lung and subjecting to additional EVLP, none of which constitute particular treatment steps. Indeed “reassessing” introduces another mental process and adding one abstract idea to another does not render the claim non-abstract. These administration steps are not particular, and are instead merely instructions to “apply” the exception in a generic way and does not integrate the mental analysis step into a practical application.
Applicant’s amendment and remarks do not address the issues raised with respect to claim 47 (see pages 12-13 of the Office action mailed 10/23/2024) regarding the recitation of “obtaining [EVLP] data relating to one or more test EVLP perfusate samples of a donor lung”, which does not require the active steps of collecting samples or carrying out immunoassays. Rather, the EVLP data may be read off of a chart and then fed into a computer to query a database of control EVLP data associated with patient outcomes. Although claim 47 recites the use of a computer to make the comparison and diagnosis, it is still drawn to a mental process (see MPEP 2106.04(a)(2)(III)(B) and rejection above). Note the claims do not require the use of artificial neural networks (ANN) or artificial intelligence (AI) to make comparisons. The reference in claim 47 to “generating the multiple classifiers/scores may include generating the multiple classifiers using the artificial intelligence technique or the machine learning technique” is optional. See recent subject matter eligibility guidance on artificial intelligence and machine learning.
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.
The provisional rejection of claims 1, 5, 12, 14, 16-20, 40-43, 47 and 71-73 on the ground of nonstatutory double patenting as being unpatentable over claims 1-7, 9, 13-24, 26, 28 and 31 of copending Application No. 18/842,351 in view of Nakajima al. and Andreasson et al. is maintained for reasons of record and the following.
Response to Arguments
Applicants’ request deferral of this issue at p.11 of the Remarks filed 11/10/2025 until other issues of patentability are resolved in their response filed 11/10/2025 is noted. However, deferral of arguments is not proper; an argument after the claims have been found otherwise allowable that obviousness type double patenting does not exist will not be considered timely. Accordingly, the rejections on the ground of nonstatutory double patenting are maintained.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTINA M BORGEEST whose telephone number is (571)272-4482. The examiner can normally be reached M-F 9-5:30 EDT.
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