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 .
Response to Amendment
Claims 1, 8, 12, 14, 16 and 19 have been amended, claims 2-6, 9-11 and 18 have been canceled and claims 21-26 have been newly added in the response filed 09 February 2026. Claims 1, 7-8, 12-17 and 19-26 are currently pending. Claims 14 and 19 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and/or species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 28 May 2024. Claims 1, 7-8, 12-13, 15-17 and 20-26 are under consideration in the instant Office action.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Any objection or rejection of record which is not expressly repeated in this action has been overcome by Applicant’s response and withdrawn.
Applicant’s arguments filed 09 February 2026 have been fully considered but are not found to be persuasive.
Drawings
Replacement drawings were received on 09 February 2026. These drawings are not acceptable for the reasons previously noted.
The drawings are objected to because they do not comply with 37 CFR 1.84(a)(1):
Black ink. Black and white drawings are normally required. India ink, or its equivalent that secures solid black lines, must be used for drawings;
The drawings are also objected to because they do not comply with 37 CFR 1.84(l):
(l) Character of lines, numbers, and letters. All drawings must be made by a process which will give them satisfactory reproduction characteristics. Every line, number, and letter must be durable, clean, black (except for color drawings), sufficiently dense and dark, and uniformly thick and well-defined. The weight of all lines and letters must be heavy enough to permit adequate reproduction.
It is noted that Applicant also filed the drawings as a file (drawing supplement). However, even the drawing supplement from the file are not compliant as the lines are not solid black and the clarity of the numbers/letters is not sufficient.
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.
Specification
Applicant’s amendment to the specification, filed 09 February 2026, is not compliant with 37 CFR 1.52(a)(1)(iv-v). In the Office action mailed 26 September 2024, the text in the middle of page 32 of the specification was pointed out as not being in dark ink or its equivalent (see 37 CFR 1.52(iv). The most recent amendment has not corrected the deficiency because the noted text is still in a format which is not composed of solid black lines. This is most likely due to the text being in “color” in the word processing program being used by Applicant and the result is text which, when magnified, shows that solid lines are not used and which results in text that appears fainter than the surrounding text. See below:
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352
651
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As can be seen from the above sample, the replacement text has the exact same problem as the original text. Therefore, the disclosure remains objected to for the reasons of record in the previous Office action.
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 24-25 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.
Claim 24 depends from claim 21 which is directed to a method for the diagnosis, prognosis, risk assessment and/or risk stratification of mortality of a subject and treating the subject wherein the method comprises determining the level of MR-proADM in a subject who is critically ill and who has been administered to an intensive care unit, wherein the determined level of MR-proADM is ≤ 0.88 nmol/L and stopping intensive care and releasing the subject from the ICU. Claim 24 then recites “wherein the subject is further treated with antibiotics”. This limitation is considered to be new matter. The term “antibiotics” does not appear in the instant specification as originally filed and therefore, there is no disclosure of the method of claim 21 wherein the subject is further treated with antibiotics. It is also noted that claim 21 does not diagnose that the subject has an infection where the treatment would necessarily be treatment with antibiotics so the limitation in claim 24 is confusing as the subject in claim 21 was released from ICU. Regardless, the claim is considered new matter and support could not be found on any of the pages indicated in Applicant’s response.
Claim 25 depends from claim 1 which is directed to a method for the diagnosis, prognosis, risk assessment and/or risk stratification of mortality of a subject and treating the subject wherein the method comprises determining the level of MR-proADM in a subject who is critically ill and who has been administered to an intensive care unit, wherein the determined level of MR-proADM is >0.88 nmol/L and keeping the subject in ICU. Claim 25 then recites “wherein the subject is further treated with mechanical ventilation, vasopressors and/or renal replacement therapy”. This limitation is considered to be new matter. The specification at no point contemplates measuring MR-proADM, making a determination of the level of MR-proADM and then, based on the determination, treating the subject as currently claimed. The disclosure only discusses the claimed interventions in the context of baseline demographics and clinical data associated with the study population of subjects (see for example pages 63-64). The specification also notes the percentage of patients who received the interventions during ICU stay (see page 67). This disclosure does not support the new claim directed. The specification was additionally reviewed at the pages indicated in Applicant’s response which assert support. However, no such support was found and therefore, the claim is considered new matter.
Claims 1, 7, 8, 12, 13, 15-17, 20-26 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 determining risk assessment, does not reasonably provide enablement for diagnosis, prognosis or risk stratification of mortality of a subject as currently claimed. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make/use the invention commensurate in scope with these claims.
Claim 1 has been amended to recite a “method for the diagnosis, prognosis, risk assessment and/or risk stratification of mortality of a subject and treating the subject” wherein the method comprises the determination of MR-proADM in a critically ill subject suffering from a disease/medical condition and who has been admitted to an ICU and wherein the level of MR-proADM is determined with 12 hours of admission of the subject to the ICU; if the subject has a level of MR-proADM greater than 0.88 nmol/L, this is stated to be an indication of an increased risk that mortality occurs or will occur with 28 days and the subject is kept on the ICU.
Claim 1 does not include any steps which would provide for a diagnosis of any disease or condition. The claims do not include any indication of what elevated levels of MR-proADM are to be diagnostic for. Claim 12 defines the disease from which the subject in claim 1 is suffering, however, a level of MR-proADM which is greater than 0.88 nmol/L is not diagnostic for the conditions listed in claim 12. Adrenomedullin is a biomarker for vascular dysfunction, tissue congestion and severe illness and MR-proADM can be elevated in a subject who is critically ill due to a number of different causes but measurement of MR-proADM alone, regardless of levels, will not provide a diagnosis of any particular disease/condition. None of the dependent claims provide any additional method steps which would result in the diagnosis of any disease or condition. Claim 21 is similar to claim 1, but makes a determination that the MR-proADM is equal to or less than 0.88 nmol/L and that this level is indicative of the subject surviving within 28 days and therefore stopping intensive care and releasing the subject from the ICU. None of the claims dependent from claim 21 add any method steps which would result in the diagnosis of any disease or condition. Therefore, the claims are not enabled for methods of diagnosis.
Likewise, none of the claims recite any limitations which provide for prognosis of a subject. Prognosis is a prediction of how a particular disease/condition will progress and clinical outcomes or the prospect of recovery from a disease/injury/condition. As the claims do not include any diagnosis of a disease, it is not clear how the method could result in a prognosis of a disease/condition when there is no identified disease/condition. The claimed method measures the level of one protein in an individual, and while that protein level may have an associated risk of mortality associated with it, the level of MR-proADM has not been found to be predictive of disease prognosis in any and all diseases/conditions in which MR-proADM may be elevated. Prognosis is determined on the basis of a number of different factors which can include age, sex, race, ethnicity, general health conditions, disease stage/grade, presence of comorbidities and treatment outcomes. In the instant claims, none of these factors are considered or measured or identified and therefore, one of ordinary skill in the art would not readily conclude that the claimed method would provide for a method of prognosis and therefore, the claims are not enabled for such.
The claims are also directed to a method of risk stratification of mortality of a subject based on the determination of the level of MR-proADM in a subject (method of claim 1 is identified above). However, risk stratification is the process of systematically categorizing individuals or populations into groups based on their probability of experiencing a specific outcome. The instant claims do not achieve a risk stratification of morality as there is no grouping of subjects nor is there any determination of probability of any particular outcome. Therefore, the claims are also not enabled for a method of risk stratification.
Claims 1, 7, 8, 12, 13, 15-17, 20-23 and 26 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 determining risk assessment, does not reasonably provide enablement for treating a subject as currently claimed. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make/use the invention commensurate in scope with these claims.
Claim 1 has been amended to recite a “method for the diagnosis, prognosis, risk assessment and/or risk stratification of mortality of a subject and treating the subject” wherein the method comprises the determination of MR-proADM in a critically ill subject suffering from a disease/medical condition and who has been admitted to an ICU and wherein the level of MR-proADM is determined with 12 hours of admission of the subject to the ICU; if the subject has a level of MR-proADM greater than 0.88 nmol/L, this is stated to be an indication of an increased risk that mortality occurs or will occur with 28 days and the subject is kept on the ICU. Claim 21 is similar to claim 1 except that a determined level of MR-proADM which is less than or equal to 0.88 nmol/L is indicative for the subject to survive within 28 days and stopping intensive care and releasing said subject from the ICU.
None of the method claims actually include a limitation which treats the subjects recited in the methods. While claims 1, 21 and 23 indicate a location of where the subject is to be placed (ICU or general ward), this is not a recitation of treatment but rather a location. The fact that a subject is admitted to the ICU is not a recitation of a treatment of a subject as no particular intervention is indicated or suggested by the placement of a subject in an ICU or in a general ward of a hospital. Therefore, the claimed methods are incomplete and not enabled for treating a subject because the claims do not recite any limitations which result in the treatment of a subject.
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, 7, 8, 12-13, 15-17, 20-26 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 instant claims are indefinite as the recited methods are incomplete as they require diagnosis, prognosis, risk stratification and treatment of a subject (independent claims 1 and 21), yet the claims fail to include any method steps which achieve the stated intent of the method. Dependent claims 7, 8, 12-13, 15-17, 20, and 22-26 are indefinite for depending on an indefinite claim.
Claim 21 is indefinite for the recitation of “is indicative for the subject to survive within 28 days”. The metes and bounds of “to survive within 28 days” is unclear.
Claim 21 is indefinite for the recitation of “stopping intensive care”. The claim does not state what “intensive care” is meant to encompass and therefore, it is unclear what the metes and bounds of stopping such care would be.
Claim 22 is indefinite for the limitation of “calculate a diagnostic score for said subject based on the determined level of MR-proADM”. The claim does not indicate what the score is to be diagnostic for and there is no information for how such a score is to use the level of MR-proADM to calculate a score. Therefore, the metes and bounds of the claim are indefinite.
Claim 23 is indefinite for the recitation of “transferred to a general ward”. The metes and bounds of what is encompassed by “a general ward” are unclear. Does this mean that a subject could be transferred to labor and delivery (is this a “general ward”) or the psychiatric ward (is this a “general ward”)?
Claim 26 is indefinite in that it is directed to the method of claim 1, “wherein a change of the level of MR-proADM is indicative of patient prognosis”. The claim is unclear and indefinite as claim 1 has a single measurement of MR-proADM and therefore, it is unclear how a change in level is to be realized. In order to determine a change, more than one measurement would need to be taken. Additionally, the claim is indefinite as there is no step or explanation as to how a change would indicate prognosis of an undefined disease.
Claim 8 is indefinite for reciting “determining the sequential organ failure assessment (SOFA) score of the subject; and increasing the determined SOFA score”. A SOFA (Sequential Organ Failure Assessment) Score has a defined meaning in the art and its calculation has a recognized methodology based on measurement of various parameters for the different organ systems (respiratory, coagulation, hepatic, cardiovascular neurological and renal) related to organ dysfunction to provide an assessment of the severity of organ dysfunction or how quickly the organ is failing. There are no provisions for “increasing” a SOFA score and the metes and bounds of “increasing” a SOFA score cannot be determined. The specification states at page 84:
The assessment of organ failure by using the SOFA score was recently proposed by the SEPSIS-3 consensus to identify high risk patients with suspected infection [15]. Our results show that a “positive” MR-proADM value may improve the ability of SOFA to predict mortality in sepsis. Interestingly, a combination of MR-proADM with clinical scores such as PSI or CURB-65 also performed better than the clinical scores alone in patients with Community Acquired Pneumonia (CAP) or lower respiratory tract infections (LRTI) [12] [19] [20] [21]. As a result, MR-proADM could be used as a reliable risk-stratification tool with the ability to predict mortality or adverse events and to guide clinical decisions. Further clinical studies evaluating strategies combining MR-proADM with other classical severity scores and/or biomarkers for improving the recognition and prognostication of sepsis are therefore warranted [22] [23].
Based on the disclosure of the instant specification, “increasing the determined SOFA score” is indefinite as there is no procedure for doing so as well as the requirement for further clinical studies to evaluate strategies for doing so.
Response to Arguments
Applicant argues at page 10 of the response that claim 8 has been amended and that “the meaning of the SOFA score per se is not modified” and therefore claim 8 is clear. Applicant’s argument has been fully considered but is not considered persuasive. Claim 8 requires one to increase the score, but the metes and bounds of this are indefinite because there is no guidance for how to increase the score or to what degree the score will be increased. Applicant also asserts at page 10 of the response that further clinical studies are not needed for generating a modified SOFA score and that the portion of the specification which was cited in the rejection refers to other severity scores and/or biomarkers other than SOFA. Applicant’s comments are noted, but they do not remedy the issue that “increasing the determined SOFA score” is an indefinite limitation for the reasons provided above.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 26 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 26 is directed to the method of claim 1, “wherein a change of the level of MR-proADM is indicative of patient prognosis”. Claim 26 does not further limit the subject matter of claim 1 as there is no additional measurement being made in claim 26. The recitation in the wherein clause is merely a description or characterization of a possible measurement which has not been made/performed. Therefore, it does not appear that claim 26 places any material limitation on claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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, 7-8, 10, 12, 13, 15-17, 20-23 and 26 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a law of nature without significantly more. The claim(s) recite(s) determining in a sample whether the level of MR-proADM is ≤ about 0.88 nmol/L or is > about 0.88 nmol/L. This threshold level is a law of nature. This judicial exception is not integrated into a practical application because the claimed method does not act upon this law of nature.
MPEP 2106 is directed to Patent Subject Matter Eligibility. Regarding the MPEP at 2106, in determining what concept the claim is “directed to,” we first look to whether the claim recites:
(1) any judicial exceptions, including certain groupings of abstract ideas (i.e., mathematical concepts, certain methods of organizing human activity such as a fundamental economic practice, or mental processes); and
(2) additional elements that integrate the judicial exception into a practical application (see MPEP § 2106.05(a)-(c), (e)-(h)).
Only if a claim (1) recites a judicial exception and (2) does not integrate that exception into a practical application, do we then look to whether the claim contains an “inventive concept’ sufficient to ‘transform’ the claimed judicial exception into a patent-
eligible application of the judicial exception. Alice, 573 U.S. at 221 (quoting Mayo, 566 U.S. at 82). In so doing, we thus consider whether the claim:
(3) adds a specific limitation beyond the judicial exception that is not
“well-understood, routine, conventional” in the field (see MPEP § 2106.05(d)): or
(4) simply appends well-understood, routine, conventional activities
previously known to the industry, specified at a high level of generality, to the
judicial exception.
See MPEP 2106.
Regarding Step 1 of the Guidance, the claims are directed to the statutory category of a process as the claims are directed to a method.
Regarding Step 2A, prong one, the claims describe and recite the judicial exception of a law of nature/natural phenomenon in claims 1 and 21 and a mental step of determining (line 5 of claim 1; line 4 of claim 21). Claim 8 additionally recites a mental step of generating a score.
Claim 1 recites determining in a sample obtained from a subject whether the level of MR-proADM is > 0.88 nmol/L. Claim 21 recites determining in a sample obtained from a subject whether the level of MR-proADM is ≤ 0.88 nmol/L. The threshold level of 0.88 nmol/L is the law of nature/natural phenomenon recited in the instant claim. Information which is gleaned from a subject’s MR-proADM level based on being less than or greater than the stated threshold of 0.88 nmol/L is a natural phenomenon that exists apart from any human action (as in Mayo Collaborative Services v. Prometheus).
Note that the Courts have held that steps that can be performed by a human using mental processes or basic critical thinking, or intangible verbal communication are types of activities that represent abstract ideas. Claims 1 and 21 recite a method comprising “determining”. Neither the specification nor the claims set forth a limiting definition for “determining” and the claim does not set forth how “determining” is accomplished. The claims do include the recitation of “using an immunoassay”, however, and assay cannot make a determination of whether a value is above/below a given value as it is merely a tool that would measure the protein. The broadest reasonable interpretation of the “determining” step is that this step may be accomplished mentally by critical thinking processes. The “determining” may also be accomplished verbally. Such mental processes and verbal communication are abstract, having no particular concrete or tangible form. For instance, one may read information in a report or database regarding protein levels by determining whether a subject has a particular level of protein in a blood sample. Thus, the “determining” step encompasses an abstract idea/process.
Applicant’s attention is directed to the Association for Molecular Pathology (AMP) and ACLU v. USPTO and Myriad Genetics (Fed. Cir. 2012)) wherein it is stated at 56-57:
We renew our conclusion that Myriad’s claims to “comparing” or “analyzing” two gene sequences fall out-side the scope of § 101 because they claim only abstract mental processes. See Benson, 409 U.S. at 67 (“Phenomena of nature, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work.”). The claims recite, for example, a “method for screening a tumor sample,” by “comparing” a first BRCA1 sequence from a tumor sample and a second BRCA1 sequence from a non-tumor sample, wherein a difference in sequence indicates an alteration in the tumor sample. ’001 patent claim 1. This claim thus recites nothing more than the abstract mental steps necessary to compare two different nucleotide sequences: one looks at the first position in a first sequence; determines the nucleotide sequence at that first position; looks at the first position in a second sequence; determines the nucleotide sequence at that first position; determines if the nucleotide at the first position in the first sequence and the first position in the second sequence are the same or different, wherein the latter indicates an alteration; and repeats the process for the next position. (Emphasis added).
Additionally, in In re BRCA1- & BRCA2-Based Hereditary Cancer Test Patent Litigation, 774 F.3D 755 (2014), the Court held that:
Having determined that the comparison steps of claims 7 and 8 are abstract ideas, we move to the second step of Alice and ask whether the particular mechanism for the comparisons added by claims 7 or 8 renders the claims patent-eligible. For this step, Alice dictates that we ask whether the remaining elements, either in isolation or combination with the other non-patent-ineligible elements, are sufficient to “‘transform the nature of the claim’ into a patent-eligible application.” Alice, 134 S. Ct. at 2355 (quoting Mayo, 132 S. Ct. at 1297). There must be a further inventive concept to take the claim into the realm of patent-eligibility. Id. at 2355. The second paragraph of claim 7 describes the way in which the sequences are compared: they are compared by 1) hybridizing a BRCA gene probe and 2) detecting the presence of a hybridization product. Similarly, claim 8 requires 1) amplification of the BRCA1 gene and 2) sequencing of the amplified nucleic acids. The non-patent-ineligible elements of claims 7 and 8 do not add “enough” to make the claims as a whole patent- eligible. (Emphasis added).
Thus, the claims recite and are directed to the patent-ineligible concept of a law of nature / natural phenomenon.
Regarding Step 2A, prong two, having determined that the claims recite a judicial exception, it is then determined whether the claims recite additional elements that integrate the judicial exception into a practical application. Here, the claims do not integrate the recited judicial exceptions into a practical application of the exception(s). For example, the claims do not practically apply the recited law of nature/natural phenomenon by including a step of treatment. The claims do not integrate the judicial exception into a practical application because it does not rely on, use or implement the judicial exception in any manner. Claims 1 and 21 recite treating the subject, however, the claims do not provide a treatment. Claim 1 recites “wherein the subject is kept on the ICU”, however, this is not a treatment but rather a location and not an indication of what therapy is being administered. Claim 21 recites “stopping intensive care and releasing said subject from the ICU” but again, this is not a discontinuation of therapy but rather a change of location for the patient. Claim 23 recites that “the subject is transferred to a general ward” but this is a change of location for the patient. The claims as a whole are not considered to recite any additional steps or elements that amount to significantly more than routine and conventional activity and do not add something “significantly more” so as to render the claims patent eligible.
The method includes mental steps as they could be performed by merely reviewing data mentally or using a computer. In addition, such steps are judicial exceptions as given their broadest reasonable interpretation, they do not clearly go beyond mental activity and add nothing specific to the law of nature/natural phenomenon other than what is well-understood, routine, conventional data gathering and analysis, previously engaged in by those in the field.
Regarding Step 2B, the next question is whether the remaining elements/steps – i.e., the non-patent-ineligible elements/steps – either in isolation or combination, amount to significantly more than the judicial exception. Here, the claims as a whole are not considered to recite any additional steps or elements that amount to significantly more than routine and conventional activity and do not add something “significantly more” so as to render the claims patent-eligible. The claims do not require performing any specific, non-conventional transformative active process steps.
Claim 1 encompasses performing any type of immunoassay determine the recited protein levels. However, methods for determining protein levels by use of immunoassay were well-known, routine and conventional in the prior art as evidenced by the instant specification beginning at page 18. Specifically, the specification at page 35 states:
The level of the markers, e.g. the at least one histone or the fragment thereof and/or the proADM or the fragment thereof, can be determined by any assay that reliably determines the concentration of the marker. Particularly, mass spectrometry (MS) and/or immunoassays can be employed as exemplified in the appended examples. As used herein, an immunoassay is a biochemical test that measures the presence or concentration of a macromolecule/polypeptide in a solution through the use of an antibody or antibody binding fragment or immunoglobulin.
The majority of the claims do not recite actual physical steps related to the determination of the recited proADM levels. The judicial exception is the comparison of the measured proADM level with the threshold value of 0.88 nmol/L. “Elements or steps that are well-understood, purely conventional, and routinely taken by others in order to apply the natural principle, or that only limit the use to a particular technological environment (filed-of-use), would not be sufficiently specific. See Mayo, 566 U.S. at , 132 S.Ct. at 1294, 101 USPQ2d at 1968.”
Applicant’s attention is again directed to the Federal Circuit decision for In re BRCA1- & BRCA2-Based Hereditary Cancer Test Patent Litigation which noted that
“the claims contain no otherwise new process for designing or using probes, primers or arrays beyond the use of BRCA1 and BRCA2 sequences in these processes.”
In other words, the naming of particular targets – e.g., the URI gene - does not add an inventive concept to the recited judicial exceptions since it was routine and conventional at the time the invention was made to use reagents that will detect particular targets.
See also Ariosa Diagnostics, Inc. v. Sequenom, Inc., F. Supp. 2d, 2013 WL 5863022, at *10 (N.D. Cal. Oct. 30, 2013) noting that "had the inventors of the [patent-in-suit] created an innovative method of performing DNA detection while searching for paternally inherited cffDNA, such as a new method of amplification or fractionation, those claims would be patentable.”
Note that this decision was affirmed by the Federal Circuit (No. 2014-1139, -1144. June 2015) wherein it is stated that “Where claims of a method patent are directed to an application that starts and ends with a naturally occurring phenomenon, the patent fails to disclose patent eligible subject matter if the methods themselves are conventional, routine and well understood applications in the art.”
Further, the steps of determining protein levels constitutes a data gathering step required to apply the law of nature / natural phenomenon.
In Mayo v. Prometheus, the Supreme Court stated: "[t]o put the matter more succinctly, the claims inform a relevant audience about certain laws of nature; any additional steps consist of well understood, routine, conventional activity already engaged in by the scientific community; and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately."
This is similar to the present situation wherein the additional steps and elements are recited at a high degree of generality and are all routine, well understood and conventional in the prior art. The recited steps and elements do not provide the inventive concept necessary to render the claims patent eligible. See also Genetic Technologies Ltd. v. Merial L.L.C., 818 F.3d at 1377, 1379 (Fed. Cir. 2016).
For the reasons set forth above, when the claims are considered as a whole, the claims are not considered to recite something significantly more than a judicial exception and thereby are not directed to patent eligible subject matter.
Response to Arguments
Applicant argues at page 11 that claim 1 is not directed to a law of nature. Applicant’s argument has been considered, but is not persuasive. The rejection did not state that the claims are directed to a law of nature. However, the claims do describe and recite the judicial exception of a law of nature/natural phenomenon (“wherein the level of MR-proADM….indicates an increased risk that mortality occurs or will occur within 28 days” and “wherein the level of MR-proADM … is indicative for the subject to survive withing 28 days”).
Applicant asserts that claim 1 does not recite a mental process “because the steps are not practically performed in the human mind”. Applicant’s argument has been fully considered, but is not found persuasive. While the measuring of the level of MR-proADM is performed using an immunoassay, the “determination” step is the mental step because one must make an assessment of whether the level is above or below the stated value, which is the mental process.
Applicant asserts that the recitation of a cutoff value in claim 1 is useful for guiding early clinical decisions and therefore “amended claim 1 is integrated into a practical application”. Applicant’s argument has been fully considered, but is not found persuasive. The limitation regarding whether or not the MR-proADM is above or below a given value being indicative of the probability of a subject surviving or dying within 28 days is the judicial exception and the claims do not integrate the judicial exception into a practical application as alleged.
At page 12 of the response, Applicant asserts that the step of “keeping the subject on the ICU” “recites a step of treatment”. Applicant’s argument has been fully considered, but is not found persuasive. The presence of a subject on the ICU does not convey the act of any particular therapeutic intervention or treatment being indicated by the measurement of MR-proADM. The placement of the subject in the ICU is taking the judicial exception and applying it as the judicial exception (subject has an increased risk that mortality occurs or will occur within 28 days) means that the subject is critically ill and critically ill subjects are cared for in the ICU. However, keeping someone on the ICU or releasing a patient from the ICU (claim 21) is not a treatment as alleged by Applicant. Additionally, such limitations do not impose a meaningful limit on the judicial exception as the placement of a subject on the ICU or the act of releasing someone from the ICU is merely applying the judicial exception, which is indicative of the severity of a subject’s illness.
Applicant argues at page 13 of the response that claim 1 and dependent claims amount to significantly more than the judicial exception because the claimed steps go beyond routine and conventional activity. Applicant asserts that the claimed method shows a faster, objective, and precise method for the prediction of an adverse event, thereby reducing mortality rates. Applicant’s argument has been fully considered, but is not found persuasive. The correlation of MR-proADM concentrations which are less than or equal to 0.88 nmol/L surviving up to 28 days is the judicial exception as is the corollary of MR-proADM concentrations which are greater than 0.88 nmol/L having an increased risk that mortality occurs within 28 days. This judicial exception does not reduce mortality rates as asserted by Applicant and there is no evidence of this conclusion in the instant specification.
Applicant argues that the claims are analogous to those in Endo Pharmaceuticals Inc. v. Teva Pharmaceuticals USA Inc. and Vanda Pharmaceuticals Inc. v. West Ward Pharmaceuticals International Ltd. because these cases used a judicial exception to identify patients in need of a particular treatment, and then administered the treatment to the identified patients. Applicants arguments have been fully considered, but are not found persuasive. The instant claims do not identify and then administer any particular treatment to the identified patients and there is no particularity to placement of a subject on the ICU or in any other part of the hospital. Placement of a patient on the ICU or release of a patient from the ICU is not a treatment as such a placement does not treat the medical condition the patient is suffering from.
Applicant argues at the bottom of page 14 of the response that the 0.88 nmol/L threshold is not merely a law of nature “but rather an empirically-derived clinical decision point selected to achieve a specific clinical objective”. Applicant asserts that the cut-off was selected because it provided a sensitivity of 100% in identifying non-survivors in the AUROC. Applicant’s argument has been fully considered, but is not found to be persuasive. The numerical value of 0.88 nmol/L is a plasma level of MR-proADM above which indicates that a patient is critically ill. Being critically ill means that a subject has a high risk of imminent death if urgent medical care is not provided. While it is appreciated that Applicant may have performed statistical analysis to arrive at this particular value, the act of statistical analysis to discover the judicial exception does not mean that it is not a judicial exception or natural phenomenon. Applicant asserts that this “cut-off may be especially useful for guiding early clinical decisions” however, neither the claims nor the instant specification disclose any clinical decisions regarding treatment which would reduce the risk of mortality which are based off of the determination that a subject has a particular MR-proADM level either above or below the 0.88 nmol/L cut-off.
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.
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Claims 1, 8, 15-17 and 20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 and 8 of U.S. Patent No. 11,041,867. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of ‘867 encompass the instant claims. ‘867 claims a method of detecting proADM (claim 1) in a subject in need thereof, comprising determining the level of proADM in the subject using an immunoassay (see claim 2). While ‘867 does not explicitly state that the subject is critically ill and suffering from a disease or medical condition who has been admitted to an intensive care unit, claim 1 does recite a “subject in need thereof” and reading the claim in light of the specification, this subject is clearly encompassed by “a subject in need thereof”. ‘867 makes a determination of whether the level of proADM is greater than 0.88nmol/L (claim 8), which necessarily includes making a determination of whether the level of proADM is less than 0.88nmol/L, as this is a mental process when viewing the level in the comparison. ‘867 recites that the assay is performed in homogenous or heterogeneous phase (claim 3) and that the method of detecting proADM also includes a determination of SOFA score (claim 1). While ‘867 does not specifically state that the sample is a body fluid, blood, plasma or urine, the disclosure of ‘867 clearly indicates as such and the claims would have been read in light of the specification as well as the fact that those skilled in the art would readily recognize that immunoassay is typically performed on liquid samples which are typically blood products.
The instant claims differ from those of ‘867 in that the subject of claim 1 is critically ill and has been admitted to an ICU. However, the method of ‘867 detects proADM and based on the level of proADM, the subject is diagnosed as having an increased risk of an adverse event within 28 days from when the sample was obtained and claim 9 lists the various events. The events which are listed are events which would result in the subjects being admitted to an ICU, therefore, one ordinary skill in the art would reasonably apply the method of ‘867 to subjects who are critically ill, including those in an ICU.
Therefore, the instant claims would have been obvious over the claims of ‘867 as the recited method steps and elements are claimed in ‘867 and because applying the method of ‘867 to subjects who have been admitted to an ICU would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Response to Arguments
Applicant argues at page 18 that the features of determining the level of MR-proADM within 12 hours of admission to the ICU or that the subject is kept in an ICU are not recited in the claims of ‘867. Applicant’s argument has been fully considered, but is not found persuasive. While these elements related to the subject in the method are not recited in the method of ‘867, it would have been obvious to perform the method of ‘867 in this patient population as the method of ‘867 identifies critically ill subjects. A subject who has been admitted to an ICU is a critically ill subject and it would have been obvious to practice the method of ‘867 on such a subject. The method of ‘867 also identifies an adverse event will happen within 28 days, therefore, the decision to keep the subject in an ICU would be an obvious conclusion to arrive at based on the method of ‘867. Lastly, when a critically ill subject arrives at a medical facility, it is routine to perform diagnostic tests as soon as possible, including within 12 hours, therefore, the instant claims would have been obvious over the claims of ‘867 for the reasons provided and therefore, the claims are not patentably distinct from those of ‘867.
Claims 1, 10, 12-13 and 15-16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 and 5-7 of U.S. Patent No.12,265,092. Although the claims at issue are not identical, they are not patentably distinct from each other for the following reasons.
Both sets of claims recite methods comprising measuring MR-proADM in a sample from a subject and determining if the level of MR-proADM above a threshold 0.88 nmol/l in patients admitted to the ICU. Both sets of claims further recite measurement of PCT levels and other variables which are included in SOFA scoring. The claims differ in that the claims of ‘036 recite many treatments and/or measuring limitations that are recited in the alternative, wherein such limitations are not recited in the instant claims. However, insofar as these limitations are recited in the alternative in the copending claims, the copending claims are still anticipatory. Accordingly, the copending claims reasonably suggest the instant claims.
Response to Arguments
Applicant asserts that the patient of the ‘092 method has not already been admitted to an ICU and the method of ‘092 does not make any determination of whether or not the subject should be kept in an ICU and it does not determine MR-proADM levels within 12 hours of ICU admission.
Applicant’s argument has been fully considered, but is not found persuasive. While these elements related to the subject in the method are not recited in the method of ‘092, it would have been obvious to perform the method of ‘092 in this patient population as the method of ‘092 identifies critically ill subjects. A subject who has been admitted to an ICU is a critically ill subject and it would have been obvious to practice the method of ‘092 on such a subject. Lastly, when a critically ill subject arrives at a medical facility, it is routine to perform diagnostic tests as soon as possible, including within 12 hours, therefore, the instant claims would have been obvious over the claims of ‘092 for the reasons provided and therefore, the claims are not patentably distinct from those of ‘092.
Conclusion
No claim is allowed.
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.
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/Christine J Saoud/Primary Examiner, Art Unit 1645
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