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 .
DETAILED ACTION
The amendment to the claims filed after non-final office action on July, 15 2025 is acknowledged. Claims 1, 3 were amended, claims 2, 5-9 were canceled and claims 1, 3-4, 10-13 are pending in the instant application.
The restriction requirement was deemed proper and made FINAL previously. Claims 1, 3-4, 10-13 are examined on the merits of this office action.
Withdrawn Rejections
The rejection of claim(s) 1, 3-4, 10, 12 remain rejected under 35 U.S.C. 102 (a)(1) as being unpatentable over EU Clinical Trials Register, referred to as “EU” in rejection (EudraCTNumber 2010-019527-58, available online 04-15-2011, cited in Applicant’s IDS) as evidenced by Proteo Biotech AG (Proteo Biotech AG: EMPIRE study includes first coronary bypass patients, News from 8/16/2011, cited in Applicant’s IDS) and as evidenced by Uniprot Protein Database (Uniprot, Protein Accession P19957, accessed on November 16, 2020, amino acids 61-117, cited in Applicant’s IDS) is withdrawn in view of amendment of the claims filed July 15, 2025.
The rejection of claim(s) 1, 3-4 and 10-13 under 35 U.S.C. 103 as being unpatentable over EU Clinical Trials Register, referred to as “EU” in rejection (EudraCTNumber 2010-019527-58, available online 04-15-2011, cited in Applicant’s IDS) as evidenced by Proteo Biotech AG (Proteo Biotech AG: EMPIRE study includes first coronary bypass patients, News from 8/16/2011, cited in Applicant’s IDS) and as evidenced by Uniprot Protein Database (Uniprot, Protein Accession P19957, accessed on November 16, 2020, amino acids 61-117, cited in Applicant’s IDS) in further view of Rabinovitch (WO1999043308 A2, cited in Applicant’s IDS) is withdrawn in view of amendment of the claims filed July 15, 2025.
The rejection of claims 1, 3-4 and 10 under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Cowan (Volume 97, Number 11, June 1996, 2452–2468, cited in Applicant’s IDS) as evidenced by Uniprot Protein Database (Uniprot, Protein Accession P19957, accessed on November 16, 2020, amino acids 61-117, cited in Applicant’s IDS) in view of Alonso (Am J Pathol. 1977 May; 87(2): 415–442, cited in Applicant’s IDS) is withdrawn in view of amendment of the claims filed July 15, 2025.
New Rejections
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 3-4, 10-13 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.
Claim 1 recites the limitation "the rise" in line 7 There is insufficient antecedent basis for this limitation in the claim as reference to a rise was removed from the claims. Claims 3-4, 10-13 are also rejected due to their dependence on claim and 1 and not further clarifying this point of confusion.
Additionally, claim 1 recites “wherein the human subject has a measured plasma troponin I and/or troponin T levels of above 0.04 ug/mL, wherein the rise in troponin I and/or troponin T levels is not associated with an increase in elastase activity in serum; and wherein the administration of elafin inhibits the further release of the troponin I and/or troponin T. Claim 1 is indefinite because the temporal relationship between the “measured plasma troponin I and/or troponin T level”, the “administration of elafin”, and the cardiac event causing troponin release is unclear. The claims recite a subject “having a measured troponin level greater than 0.04 ug/mL” and that administration of elafin “inhibits the further release” of troponin. However, dependent claim 13 specifies that elafin is administered prior to coronary bypass surgery, which surgery is the event that causes troponin release. It is therefore ambiguous whether the “measured” troponin level refers to a value obtained before, during or after the surgical procedure or administration. Because the point in time to which “further release” relative cannot be determined, the scope of the claim is not reasonably certain rendering claim 1 and all dependent claims (3-4, 10-13) indefinite.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s)1, 3-4, 10-13 is/are rejected under 35 U.S.C. 103 as being unpatentable over EU Clinical Trials Register, referred to as “EU” in rejection (EudraCTNumber 2010-019527-58, available online 04-15-2011, cited in Applicant’s IDS) as evidenced by Proteo Biotech AG (Proteo Biotech AG: EMPIRE study includes first coronary bypass patients, News from 8/16/2011, cited in Applicant’s IDS) and as evidenced by Uniprot Protein Database (Uniprot, Protein Accession P19957, accessed on November 16, 2020, amino acids 61-117, cited in Applicant’s IDS) in view of Rabinovitch (WO1999043308 A2, cited in Applicant’s IDS) and Sadony (European Journal of Cardio-thoracic Surgery 13 (1998) 57–65).
Claim 1 interpretation: claim 1 claims “A method of treating a heart disease or disorder comprising administering elafin (SEQ ID NO:1) parenterally or systemically to a human subject in need thereof, wherein the heart disease or disorder involves damage to a cardiac muscle and wherein the heart disease or disorder is associated with a cell damage and/or cell death leading to troponin I and/or troponin T release and wherein the human subject has a measured plasma troponin I and or T levels of above 0.04 ug/mL, wherein the rise is not associated with an increase in elastase activity in the serum and wherein the administration of elafin further inhibits the release of the troponin I and/or troponin T”. Claim 4 claims wherein the heart disease or disorder is selected from the group consisting of….myocardial injury due to heart surgery selected from a coronary artery bypass surgery, a cardiovascular surgery…” Thus, based on instant claims 1 and 4, the patient population encompassed by instant claims 1 and 4 are patients undergoing coronary bypass surgery which is associated with cardiac cell damage or cell death. Please note that the measured plasma troponin is not at any required point. Thus, the troponin T could be measured in the subject following coronary bypass surgery and the measured troponin could be after surgery. Furthermore, the limitation of inhibiting further release is not necessarily absolute just as long as there is some level of inhibition.
EU is a Human Clinical trial Registry which teaches delivering elafin by infusion during cardiac bypass surgery in attempts to determine efficacy for reducing myocardial injury that results from ischemia and subsequent inflammation (see page 2, “general information about the trial”, E.2.1, “main objective of the trial”). EU teaches trial subjects as male and female adults (see “F. Population of Trial Subjects”). EU does not specifically state “humans”, however one of ordinary skill in the art would readily recognize that Clinical Trials are completed in human subjects.
EU further teaches that the “primary endpoint will be area under the curve for plasma troponin T release from time point 0 to 48 h following coronary artery bypass surgery” (see page 3, E.5.1 “primary endpoint(s)”). EU further teaches intravenous use (see page 2, “D.3.7”) which meets the limitation of parenteral administration.
Regarding claims 4 and 12, EU teaches administering during the cardiac bypass surgery (see page 2, bottom, “E.2.1”).
Regarding claim 10, EU teaches intravenous administration which meets the limitations of instant claim 10 (see page 2, “D.3.7”).
Regarding claim 1, As evidenced by Proteo Biotech AG and Uniprot, the elafin used in the clinical trial (EMPIRE) is “human identical protease inhibitor Elafin” (see attached Proteo Biotech Ag, first paragraph). As evidenced by Uniprot protein Database, human elafin comprises instant SEQ ID NO:1 (see page 3, amino acids 61-117, and amino acids 61-117 on page 7).
Please note that the limitations of “treating a heart disorder (which involves damage to a cardiac muscle)” found in instant claim 1 is an intended result of the claimed method. EU teaches the same patient population, a human patient undergoing cardiac by-pass surgery, and administering the same therapeutic, human Elafin, thus the effects of treating the disorder (which is defined as myocardial injury due to coronary bypass surgery” (claim 4) will inherently occur as a result of practicing the method of EU. MPEP § 2112 states: “Once a reference teaching a product appearing to be substantially identical is made the basis of a rejection, and the Examiner presents evidence or reasoning tending to show inherency, the burden shifts to the Applicant to show an unobvious difference ‘[t]he PTO can require an Applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his [or her] claimed product. Whether the rejection is based on inherency’ under 35 U.S.C. 102, on prima facie obviousness’ under 35 U.S.C. 103, jointly or alternatively, the burden of proof is the same…[footnote omitted].” The burden of proof is similar to that required with respect to product-by-process claims. In re Fitzqerald, 619 F.2d 67, 70, 205 USPQ 594, 596 (CCPA 1980) (quoting In re Best, 562 F.2d 1252, 1255, 195 USPQ 430,433- 34 (CCPA 1977)).”
Regarding the patient population of instant claim 1, Patients undergoing cardiac bypass surgery are considered subjects in need of reducing myocardial damage leading to troponin I release. This is further evidenced by Applicant’s specification (see paragraph 0038, 0094-0096, pgPUB and claim 12).
Regarding the limitation of claim 1 of “wherein the rise in troponin I…is not associated with an increase in elastase activity in serum” , EU is silent to an association between an increase in elastase activity and Troponin I and/or Troponin T. Nevertheless, given that there is no specific timing as to when this activity/association occurs (before or after administration of the polypeptide), EU teaches the same method of the instant claims including administering the same polypeptide to a patient undergoing cardiac surgery and thus these effects would inherently occur (see MPEP 2112.01-2112.02). This is further evidenced by the fact that human elafin, (instant SEQ ID NO:1 ) inhibits elastases as evidenced by Uniprot (see attached handout, first page, “function”).
Regarding the limitations of “wherein the rise in troponin I and/or T levels is not associated with an increase in the serine protease proteinase 3” found instant claim 3, EU does not indicate that the heart surgery is associated with an increase in serum proteinase 3. In addition, the lack of an increase of serine proteinase 3 is an intended result of the method of reducing myocardial damage in patients undergoing heart surgery with administration of elafin. EU teaches the same method of the instant claims (same therapeutic and same patient population) and thus, the desired result oriented outcome will inherently occur as a result of practicing the method of EU (see MPEP 2112.01-2112.02).
EU is silent to administering elafin via other parenteral routes of administration including subcutaneously or administering elafin prior to the coronary bypass surgery (instant claims 11 and 13). Furthermore, EU does not teach a measured specific level of troponin I and/or T of above 0.04 ug/mL.
However, Rabinovitch teaches administering elafin for the same purpose, reducing/inhibiting elastase, in humans via different parenteral routes including subcutaneous (see claim 1, 4, see page 3, lines 26-28).
Furthermore, it would have been obvious to try subcutaneous as a route of administration and also pre, during and post administration of elafin.
It has been held that under KSR that “obvious to try” may be an appropriate test under 103. The Supreme Court stated in KSR, When there is motivation “to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under § 103.” KSR Int’l Co. v. Teleflex Inc., 127 S. Ct. 1727,_,82 USPQ2d 1385, 1397 (2007).
The skilled artisan would have had reason to try subcutaneous administration with the reasonable expectation that at least one would be successful especially in light of the fact that the art teaches subcutaneous administration of elafin for the same purpose, inhibiting cardiac damage. Thus, use of subcutaneous administration of elafin for treating human patients is “the product not of innovation but of ordinary skill and common sense,” leading to the conclusion that invention is not patentable as it would have been obvious. Furthermore, it would have been obvious to try administering elafin prior to surgery, during surgery and after surgery inhibit cardiac damage as soon as possible during surgery.
Regarding the route of administration and timing of administering, these are all considered result effective variables.
It would be obvious to one of ordinary skill in the art to optimize result effective variables such as timing (pre, during and post-surgery administration) and route of administration. The MPEP states the following: Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997). Therefore, it would have been obvious to optimize the timing of administration of route of administration to achieve optimal activity and therapeutic effectiveness of the elafin in patients. For example, have the elastase inhibitor already present in the body may allow for quicker inhibition of elastase activity as opposed to administering at the time of the surgery itself. There is a motivation to optimize since it is normal desire of scientists or artisans to improve upon what is already generally known with a reasonable expectation that optimization would at least work the same.
Regarding the measured amount of troponin found in instant claim 1, EU further teaches that the “primary endpoint will be area under the curve for plasma troponin T release from time point 0 to 48 h following coronary artery bypass surgery” (see page 3, E.5.1 “primary endpoint(s)”). Furthermore, this is an association with the heart disease or disorder (i.e. troponin levels rise in patients undergoing cardiac bypass). As evidenced by Applicant’s specification, a rise in troponin levels is associated in patients that undergo cardiac surgery.
Furthermore, Sadony (see abstract) explicitly teaches quantitative measurement of cardiac troponin I levels in patients undergoing CABG, reporting values of 6.5 ng/ml at 6 H, 9.8 ng/mL at 12 h and 11.6 ng/mL at 24 after aortic unclamping for discrimination of patients with or without peri operative myocardial infarction/damage, with diagnostic sensitivities of 88-100% and specificities greater than or equal to 97%. Sadony concludes that cardiac troponin I qualifies as a reliable marker for diagnosis and quantitation of myocardial damage in CABG patients.
It would have been obvious before the effective filing date of the claimed invention to administer human elafin (SEQ ID NO:1) to patients undergoing coronary artery bypass surgery, as taught by EU, in order to reduce myocardial injury as evaluated by plasma troponin release. EU teaches that the primary endpoint of the clinical trial is the area under the curve for plasma troponin T release from 0 to 48 hours after bypass surgery, thereby explicitly disclosing measurement of troponin levels in CABG patients to assess cardiac damage.
The specific limitation requiring “the human subject has a measured plasma troponin I and/or T level above 0.04 ug/ml” would have been obvious before the effective filing date of the claimed invention, since the art collectively teaches through EU, the administration of elafin during coronary bypass surgery to reduce myocardial injury and through Sadony, the measurable post operative troponin elevations that are diagnostic of myocardial injury in the same surgical context.
Furthermore, one of ordinary skill in the art would have understood that the CABG patient population disclosed in EU inherently exhibits measured plasma troponin I and or troponin T levels above the threshold of 0.04 ug/mL, since both EU and Sadony describe the same clinical injury and same perioperative measurement of troponin as a biomarker of myocardial damage (Sadony disclosing levels above 0.04 ug/mL in the patient population). The claimed limitation merely recites the know diagnostic characterization of that patient population, which would inherently occur when practicing the method taught by EU in view Sadony.
Response to Applicant’s Arguments
Applicant argues “As discussed in section III above, the EU reference fails to disclose or suggest the treatment of a specific subset of the human population-namely, those with measured plasma troponin I and/or troponin T levels above 0.04 pg/mL. This patient subgroup is now explicitly recited in amended claim 1. The EU reference is silent on troponin levels and does not address the use of elafin in this context.
Rabinovitch does not cure this deficiency. It is entirely silent on troponin, let alone the treatment of patients with elevated troponin levels. Rabinovitch describes the use of elafin as an elastase inhibitor for treating pulmonary hypertension, and does not disclose or suggest its use in cardiac conditions involving myocardial injury, which is characterized by troponin release For at least the foregoing reasons, the cited references fail to disclose or suggest the claimed invention, and the Office has not established a prima facie case of obviousness. Applicant respectfully requests withdrawal of the rejection under 35 U.S.C. § 103.
Applicant’s arguments have been fully considered but not found persuasive. Applicant contends that the EU reference fails to disclose or suggest treatment of a specific subset of patients “having measured plasma troponin I and/or T levels above 0.04 ug/mL”. However, as discussed above, EU explicitly teaches measurement of plasma troponin T from 0 to 48 hours following coronary bypass surgery as the primary endpoint for determining myocardial injury (See EU, page 3, E.5.1 “primary endpoint”). Thus, EU inherently involves subjects experiencing post-surgical myocardial damage characterized by troponin elevation as seen in Sadony. In addition, Sadony teaches quantitative measurement of cardiac troponin I levels in CABG patients and reports mean values of 6.5 ng/mL at 6 hours, 9.8 ng/ml at 12 hours and 11.6 ng/ml at 24 hours after aortic unclamping, which are orders of magnitude greater than the threshold of 0.04 ug/mL. Sadony concludes that troponin I measurement serves to quantify myocardial injury in the same patient population. Therefore, one of ordinary skill in the art would have understood that the CABG subjects disclosed in EU necessarily exhibit some patients with troponin levels exceeding 0.04 ug/mL when measure in accordance with trial protocol. The claimed limitation merely recites a known diagnostic state that is inherent to patients undergoing coronary bypass surgery, who are the subjects described in EU and Sadony. Whether or not EU specifies the exact numeric value, such elevated troponin concentrations are a recognized physiologic results of CABG as taught by Sadony. Accordingly, the Office maintains that the limitation would have been obvious before the effective filing date of the claimed invention, since the art collectively teaches (EU) the administration of elafin during CABG and Sadony teaches the measurable post operative troponin levels diagnostic of myocardial injury in the same context. The combination therefore renders obvious the claimed subject matter.
Conclusion
No claims are 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERINNE R DABKOWSKI whose telephone number is (571)272-1829. The examiner can normally be reached Monday-Friday 7:30-5:30 Est.
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/ERINNE R DABKOWSKI/Examiner, Art Unit 1654
/JULIE HA/Primary Examiner, Art Unit 1654