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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 30 June 2026 has been entered.
DETAILED OFFICE ACTION
This Office Action is in response to the papers filed on 30 June 2026.
CLAIMS UNDER EXAMINATION
Claims 31, 34, 37-41, 44-46, 48-56 and 58-62 are pending and have been examined on their merits.
PRIORITY
Foreign document EP19153572.3, filed on 24 January 2019, is acknowledged.
WITHDRAWN REJECTIONS
The previous rejections have been withdrawn due to claim amendment.
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.
Claims 58 and 62 are rejected under 35 U.S.C. 101 because the claimed invention is not directed to patent eligible subject matter.
Based on the claim as a whole, claim 58 is determined to be directed to a law of nature/natural principle. The rationale for the determination is explained below.
Claim 58 is directed to a method of determining if the patient is administered with a sufficient amount of Glu-plasminogen to prevent or treat a thrombotic event.
Question 1: Is the claim to a process, machine manufacture or composition of matter? Yes, the invention recited in claim 58 is a process.
Question 2A Prong 1: Is the claim directed to a law of nature, a natural phenomenon, or an abstract idea (judicially recognized exceptions)? Yes, claim 58 is directed to a law of nature.
(a) The limitations in the claim that set forth the law of nature are:
The 2019 PEG explains that the abstract idea exception includes the following groupings of subject matter:
Mathematical concepts – mathematical relationships, mathematical formulas or equations, mathematical calculations;
Certain methods of organizing human activity – fundamental economic principles or practices (including hedging, insurance, mitigating risk); commercial or legal interactions (including agreements in the form of contracts; legal obligations; advertising, marketing or sales activities or behaviors; business relations); managing personal behavior or relationships or interactions between people (including social activities, teaching, and following rules or instructions); and
Mental processes – concepts performed in the human mind (including an observation, evaluation, judgment, opinion).
The claim recites administering a sufficient amount of Glu-plasminogen to prevent or treat a thrombotic event if the determined level of Glu-plasminogen is lower in comparison to the average level found throughout a control population. Comparing data to determine if Glu-plasminogen is administered is a mental process. Such mental observations and evaluations fall within the “mental processes” grouping of abstract idea set forth in the 2019 PEG. 2019 PEG Section I, 84 Fed. Reg. at 52. observations and evaluations that can be performed in the human mind (hence within the “mental processes” grouping of abstract ideas).
Question 2A Prong 2: Does the claim recite additional elements that integrate the judicial exception into a practical application? No.
The claim does not require administration of the sufficient amount of Glu-plasminogen.
Question 2B: Do the claims recite any additional elements? Yes.
With respect to Step 2B, limitations that were found to be enough to qualify as “significantly more” when recited in a claim with a judicial exception include:
Improvements to another technology or technical field.
Improvements to the functioning of the computer itself.
Applying the judicial exception with, or by use of, a particular machine.
Effecting a transformation or reduction of a particular article to a different state or thing
Adding a specific limitation other than what is well-understood, routine and conventional in the field, or adding unconventional steps that confine the claim to a particular useful application.
Other meaningful limitations beyond generally linking the use of the judicial exception to a particular technological environment.
With respect to Step 2B, limitations that were found not to be enough to qualify as “significantly more” when recited in a claim with a judicial exception include:
Adding the words ‘‘apply it’’(or an equivalent) with the judicial exception, or mere instructions to implement an abstract idea on a computer
Simply appending well-understood, routine and conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, e.g., a claim to an abstract idea requiring no more than a generic computer to perform generic computer functions that are well understood, routine and conventional activities previously known to the industry
Adding insignificant extrasolution activity to the judicial exception, e.g., mere data gathering in conjunction with a law of nature or abstract idea
Generally linking the use of the judicial exception to a particular technological environment or field of use.
Do the additional elements result in the claim amounting to significantly more?
No.
Claim 58 depends from claim 31. While claim 31 requires administration, this step is required for the mental comparison recited in claim 58. Therefore it does not amount to significantly more than the recited judicial exception.
Claim 62 recites steps i-ii of claim 58 are conducted repeatedly if the level of Glu-plasminogen is at least 10% lower in comparison the average level in a control population. A comparison is a mental process (a judicial exception).
Therefore claims 58 and 62 are not eligible subject matter under 35 USC 101.
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 34, 40, 46, 48, 49, 54, 55 and 59 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 34 recites the patient suffers from an ischemic region that “would cause” necrosis of at least a part of a tissue without Glu-plasminogen administration. The base claim requires administration of Glu-plasminogen to the same patient. It is unclear how to determine whether the ischemic region in the treated patient (claim 31) would cause necrosis of at least part of a tissue without Glu-plasminogen. The claimed method requires administration. Thus, the untreated condition recited in claim 34 does not occur. Accordingly, it is unclear ow to determine whether a particular treated patient meets the limitation recited in claim 34. Appropriate correction is required.
Claim 40 is rejected on the basis that it contains an improper Markush grouping of alternatives. A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a "single structural similarity" and a common use. The Markush grouping recited in claim 40 is improper because the alternatives defined by the Markush grouping do not share a structural/mechanistic thread linking cause and effect. The claim recites two lists with a causal "resulting in" — but the diseases in the second list don't result from stenosis/spasm of blood vessels:
Vascular/thrombotic events (embolism, stroke, myocardial infarction) can result from stenosis or spasm. Vitamin/nutrient deficiencies (vitamin D, K, H, iron deficiency) are not caused by vascular stenosis or spasm. These are nutritional/metabolic conditions with unrelated etiology. Bleeding disorders (Von Willebrand Syndrome, epistaxis, hypermenorrhea) reflect hemostatic failure, which is mechanistically different from stenosis (narrowing/occlusion). Morbus Meulengracht (Gilbert's syndrome) is a bilirubin-conjugation liver disorder. It does not have an established causal relationship to vessel narrowing or spasm. Thyroid dysfunction, migraine, and abortion (miscarriage) are each associated with vastly different, non-overlapping physiological systems. “Therapy failures in lysis therapy using plasminogen activators" isn't a disease. It is a treatment-outcome description.
Claim 40 does not recite a single unifying structural feature or common use.
For a Markush group to be proper, the alternatives must share either:
a common structural core essential to the claimed utility, or
a recognized common function/activity relevant to the invention.
The pathologies recited in claim 40 span hematology, endocrinology, hepatology, neurology, obstetrics and pharmacology-outcome categories. There is no single shared structural or functional thread. The tern “resulting” is causal, and not a structural or functional commonality recognized in the art. Appropriate correction is required.
Claim 46 recites the patient suffers from an ischemic region that “would cause” necrosis of at least a part of a tissue without Glu-plasminogen administration. The base claim requires administration of Glu-plasminogen to the same patient. It is unclear how to determine whether the ischemic region in the treated patient (claim 31) would cause necrosis of at least part of a tissue without Glu-plasminogen. The claimed method requires administration. The untreated condition recited in claim 46 does not occur. It is unclear ow to determine whether a particular treated patient meets the limitation recited in claim 46. Appropriate correction is required.
Claim 48 recites the patient suffers from an ischemic region that “would cause” 1) necrosis of at least a part of a tissue and 2) at least one thrombotic event without Glu-plasminogen administration. The base claim requires administration of Glu-plasminogen to the same patient. It is unclear how to determine whether the ischemic region in the treated patient (claim 31) would cause necrosis of at least part of a tissue without Glu-plasminogen. The claimed method requires administration. Thus, the untreated condition recited in claim 48 does not occur. Accordingly, it is unclear ow to determine whether a particular treated patient meets the limitation recited in claim 48. Appropriate correction is required.
Claim 49 recites “the thrombotic event results in an infarction”. Claim 31 recites 10-110 thrombotic events. It is unclear which thrombotic event claim 49 is referring to. The metes and bounds of the claim are unclear. Appropriate correction is required.
Rgearding claim 54: Claim 31 requires treating 10 to 100 thrombotic events and further requires that the patient has developed microthrombi. Dependent claim 54 recites administration “within one week before being subjected to an event with a risk of developing a thrombotic event”. The scope of the claim is unclear. It is unclear whether the 10-100 thrombotic events required by claim 31 must have occurred before administration of Glu-plasminogen, or whether claim 54 encompasses prophylactic administration before the occurrence of any thrombotic events. The metes and bounds of the claim are unclear. If claim 54 means the 10-100 events in the base claim do not occur, then claim 54 presents issues under 35 USC 112d. Appropriate correction is required. Claim 55 is included in this rejection because it depends from claim.
Claim 59 is rejected on the basis that it contains an improper Markush grouping of alternatives. The claim recites an “infarction of any organ”. An infarction is tissue necrosis. The claim also recites deep vein thrombosis, pelvic vein thrombosis thrombophlebitis are all venous thrombosis. Pulmonary embolism and retinal vein occlusion are consequences of thrombus. DIC and TTP are recognized thrombotic microangiopathies. These conditions share thrombosis as a pathological event. An infarction of any organ is a category that is not related to the thrombotic conditions recited in the claim. Appropriate correction is required.
Claim 59 recites “an angiopathy coincidence with thrombotic events in capillary flow path”. The metes and bounds of “coincidence with” is unclear. It is unclear what condition qualifiers as being within the claim limitation. It is unclear if the claim means the angiopathy happens at the same time as thrombotic events, occurs in the same anatomical location as the thrombotic events, or if the angiopathy is a chance occurrence (i.e. a coincidence). Appropriate correction is required.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 31, 34, 37-41, 45-46, 48-56 and 59-61 are rejected under 35 U.S.C. 103 as being unpatentable over Li et al. (previously cited; Plasminogen For Use In Preventing Or Treating Acute Thrombosis and Chronic Thrombosis. EP3395359 published as WO2017/101866) in view of Ito et al. (Combination of high-performance affinity chromatography and specific detection of proenzyme applicable to the analysis of the fibrinolytic system of human plasma. Journal of Chromatography, 386 (1987) 51-56), Kaufman et al. (previously cited) and Fukao et al. (Tissue-type plasminogen activator, type 1 plasminogen activator inhibitor and their complex in plasma with disseminated intravascular coagulation. Thromb Res. 1992 Oct 1;68(1):57-65) as evidenced by Roosevelt University (20.1 Structure and Function of Blood Vessels pages 1-10).
Li administers plasminogen to treat thrombosis ([0001]). Li teaches a human subject ([0027]). Li teaches the subject has a low level of plasminogen ([0028]). Li teaches the low level of plasminogen can be secondary (hence, acquired) ([0030] [0062]). Li teaches the administered plasminogen can be Glu-plasminogen ([0035]). At [0037] Li teaches “the plasminogen” is administered at a dose of 0.01-600 mg/kg. At [0117] Li explicitly states the plasminogen composition can be administered at a dose of 0.02 or 0.25 mg/kg. Because Li teaches a carrier is optional ([0108]), the art is interpreted to teach a dose of 0.02 mg/kg or 0.25 mg/kg plasminogen. Li teaches natural plasminogen (Glu-plasminogen ([0004]) has good function of dissolving thrombi with easy adjustment of thrombolytic strength ([0009]).
Li identifies capillary thrombosis as a type of thrombosis ([0066]) that is common in disseminated intravascular coagulation ([0068]). As evidenced by Roosevelt University, “the diameter of a capillary lumen ranges from 5–10 micrometers” (hence, less than 0.5 mm) (see section titled “Capillaries” on page 5). Therefore the art teaches a thrombotic event of a blood vessel having a diameter of less than 0.5 mm. A thrombus that occludes a capillary lumen would necessarily have a diameter constrained by the diameter of the capillary.
Li teaches a low level of plasminogen. The low level of plasminogen can be acquired. Li teaches Glu-plasminogen administration. The art does not explicitly teach the patient has a Glu-plasminogen deficiency. Li does not teach treating 10-100 microthrombi.
Ito teaches human patients with disseminated intravascular coagulation (DIC). Ito teaches the “poor condition” of the patient is reflected in the “very low” Glu-plasminogen content relative to a “normal” control. As the patient improved, the Glu-plasminogen content became “normal” (relative to control) (See Figure 3, see page 55, first paragraph).
Kaufman et al. count the number of microthrombi in human patients with disseminated intravascular coagulation (DIC) (see Abstract; see “Methods” section on page 35, left column, first two paragraphs). The art discloses human patients with at least 10, but less than 100 microthrombi (Table 7; Table 9; Table 11).
Fukao analyzed plasma in the plasma of disseminated intravascular coagulation (DIC) patients and healthy controls. The DIC plasma revealed a significant consumption of plasminogen (Abstract).
It would have been obvious to administer the Glu-plasminogen taught by Li to a DIC patient with Glu-plasminogen deficiency caused by increased consumption. Li teaches Glu-plasminogen can be administered to a patient with an acquired plasminogen deficiency. Ito teaches humans with DIC have low levels of Glu-plasminogen, while Fukao teaches DIC is associated with significant plasminogen consumption. One would administer Glu-plasminogen to restore consumed plasminogen in these patients. This motivation would have been particularly apparent in a DIC patient because such patients were known to develop extensive microvascular thrombosis between 10-100, as taught by Kaufman. One would have had a reasonable expectation of success since Ito teaches normal function is restored when Glu-plasminogen levels are restored.
It would have been obvious to administer a dose of 0.01 to 0.40 mg/kg. Li teaches a range of 0.01-600 mg/kg, and discloses explicit doses of 0.02 or 0.25 mg/kg.
Li teaches the plasminogen thrombolytic rate can be controlled by the dose of plasminogen. One would optimize the dose based on the desired level of thrombolysis. One would have had a reasonable expectation of success since Li teaches plasminogen can be administered at a dose of 0.02 or 0.25 mg/kg. One would have expected similar results since both references teach Glu-plasminogen can be administered to treat thrombolysis in human subjects. Absent evidence of criticality the claimed dose is rendered obvious. See MPEP 2144.05. Therefore claim 31 is rendered obvious.
Li teaches thrombosis causes ischemia and necrosis ([0066] [0068]). Therefore the ischemia would cause necrosis of at least part of a tissue and at least one thrombotic event without Glu-plasminogen administration. Claims 34 and 46 are included in this rejection.
Fukao teaches a patient with DIC has increased consumption. Therefore claim 37 is included in this rejection.
Li teaches Glu can be administered with Lys-plasminogen ([0035]). Therefore claim 38 is included in this rejection.
Kaufman teaches a patient with 10-100 thrombotic events. Therefore the patient is at risk of developing the conditions recited in claims 39-40 and 60.
Ito teaches a lower Glu-plasminogen level in DIC than a normal patient (a control population). Claim 41 is included in this rejection.
Li teaches capillary thrombosis. Claim 45 is included in this rejection.
Li teaches thrombosis causes ischemia and necrosis ([0066] [0068]). Therefore the ischemia would cause necrosis of at least part of a tissue and at least one thrombotic event without Glu-plasminogen administration. Claim 48 is included in this rejection.
The thrombotic events recited in claim 31 are rendered obvious. Therefor they would result in an infarction. Claim 49 is included in this rejection.
Claims 50-51 recite the cause of the thrombotic events. The claim does not distinguish the claimed microthrombi from those rendered obvious by the prior art. Therefore claims 50-51 are included in this rejection.
Thrombotic events are rendered obvious as set forth above. Therefore they cause an infarction. Claim 52 is included in this rejection.
Li teaches a dose of 0.20 mg/kg. Li teaches daily administration (hence, at least once [0049]). Therefore claims 53-54 included in this rejection.
Li teaches daily administration ([0049]). Li teaches intravenous administration ([0055]).Li teaches alternate days ([0117]). This is interpreted to read on administration daily for 15 days ([0173]). Claim 56 is included in this rejection.
Li teaches a patient with DIC. Claims 59 and 61 are rejected.
Therefore Applicant’s Invention is rendered obvious as claimed.
Claims 31, 33-34, 37-41, 44-46, 48-56 and 58-62 are rejected under 35 U.S.C. 103 as being unpatentable over Robitaille et al. (previously cited; Plasminogen Replacement Therapy For Plasminogen Deficiency. WO2017/077380 11 May 2017) in view of Li, Ito and Kaufman et al. as evidenced by Fukao et al.
Robitaille et al. teach a method for increasing the plasmatic plasminogen activity level of a plasminogen-deficient subject (see page 2, lines 4-5). Robitaille treats a human (page 9, line 26). Robitaille teaches the plasminogen-deficient subject has “an acquired deficiency” (see Abstract; see page 2, number 5; page 8, line 17). The art teaches administering a dose of Glu-plasminogen to a patient (Abstract; see page 2, line 14).
Robitaille identifies disseminated intravascular coagulation (DIC) as an acquired plasminogen deficiency (see page 15, line 6) which may cause tissue ischemia from occlusive microthrombi (see page 18, line 4). Robitaille teaches DIC causes consumption of platelets and coagulation factors (page 18, line 5). As evidenced by Fukao, plasminogen is also consumed in patients with DIC. As evidenced by instant claim 59, a subject with Disseminated intravascular coagulation (DIC) reads on claim 31.
Regarding the dose: Robitaille teaches administering a daily dose of at least 0.5 mg/kg of mass of the subject (see page 24, lines 1-2). The art teaches administering a dose that will increase plasminogen activity level by at least 1% of the normal plasminogen activity (see page 8, lines 25-29).
The deficiencies of Robitaille are:
The art does not teach the patient has 10-100 thrombotic events. The art is silent regarding the diameter of the microthrombi and vessels. The art does not teach 0.01 to 0.40 mg/kg body weight. The art does not explicitly teach a Glu-plasminogen deficiency.
Li teaches plasminogen, including Glu-plasminogen can be administered to treat thrombosis ([0035]). At [0037] Li teaches “the plasminogen” is administered at a dose of 0.01-600 mg/kg. At [0117] Li explicitly states those dose of the plasminogen composition can be administered at a dose of 0.02 mg/kg. Li teaches natural plasminogen (Glu-plasminogen ([0004]) has good function of dissolving thrombi with easy adjustment of thrombolytic strength ([0009]).
Li identifies capillary thrombosis as a type of thrombosis ([0066]) that is common in disseminated intravascular coagulation ([0068]). It is well known that “the diameter of a capillary lumen ranges from 5–10 micrometers” (hence, less than 0.5 mm) (supra). Therefore the art teaches a thrombotic event of a blood vessel having a diameter of less than 0.5 mm. A thrombus that occludes a capillary lumen would necessarily have a diameter constrained by the diameter of the capillary.
Ito teaches human patients with disseminated intravascular coagulation (DIC). Ito teaches the “poor condition” of the patient is reflected in the “very low” Glu-plasminogen content relative to a “normal” control. As the patient improved, the Glu-plasminogen content became “normal” (relative to control) (See Figure 3, see page 55, first paragraph).
Kaufman et al. count the number of microthrombi in human patients with disseminated intravascular coagulation (DIC) (see Abstract; see “Methods” section on page 35, left column, first two paragraphs). The art discloses human patients with at least 10, but less than 100 microthrombi (Table 7; Table 9; Table 11).
It would have been obvious to administer the Glu-plasminogen taught by Robitaille to a patient with Glu-plasminogen deficiency. Robitaille teaches Glu-plasminogen can be administered to a patient with an acquired plasminogen deficiency which causes consumption. Ito teaches humans with DIC have low levels of Glu-plasminogen. One would administer Glu-plasminogen to restore consumed plasminogen in these patients. This motivation would have been particularly apparent in a DIC patient because such patients were known to develop extensive microvascular thrombosis between 10-100, as taught by Kaufman. One would have had a reasonable expectation of success since Robitaille teaches Glu-plasminogen can be administered to restore normal function.
It would have been obvious to treat a patient with microthrombi with a diameter less than 1mm in blood vessels with a diameter less than 0.5 mm. One would have been motivated to do so since Robitaille teaches DIC and Li teaches thrombosis of capillaries (a vessel less than 0.5 mm in diameter) is common in these patients. A thrombus that occludes a capillary lumen would necessarily have a diameter constrained by the diameter of the capillary. One would have had a reasonable expectation of success since Robitaille teaches acquired deficiencies can be treated by Glu-plasminogen administration. One would have expected similar results since both references teach Glu-plasminogen can be administered to treat thrombolysis in human subjects.
It would have been obvious to optimize the dose taught by Robitaille. Robitaille teaches administering a dose that increases the subject plasminogen level by at least of the normal plasminogen activity. Li teaches the plasminogen thrombolytic rate can be controlled by the dose of plasminogen. One would optimize the dose taught by Robitaille based on the desired level of thrombolysis. One would have had a reasonable expectation of success since Li teaches plasminogen can be administered at a dose of 0.02 mg/kg. One would have expected similar results since both references teach Glu-plasminogen can be administered to treat thrombolysis in human subjects. Absent evidence of criticality the claimed dose is rendered obvious. See MPEP 2144.05. Therefore claim 31 is rendered obvious.
Robitaille teaches disseminated intravascular coagulation (DIC) is an acquired plasminogen deficiency (see page 15 line 6). DIC may cause tissue ischemia from occlusive microthrombi (see page 18, first paragraph). Therefore a patient with DIC is interpreted to read on a patient with an ischemic region as recited in claim 34 and 46.
Robitaille teaches acquired plasminogen deficiency may be the result of increased plasminogen consumption (see page 14, line 27). Therefore claims 33 and 37 is included in this rejection.
Regarding claim 38: Robitaille teaches administering plasminogen, preferably Glu-plasminogen, to treat a plasminogen deficiency. The art does not teach administering Glu-plasminogen in combination with Lys-plasminogen.
Li teaches Glu-plasminogen can be administered in combination with Lys-plasminogen ([0035]). Li teaches Lys-plasminogen has a higher affinity for fibrin and can be activated by plasminogen activation at a higher rate ([0004]).
It would have been obvious to combine Lys-plasminogen with the Glu-plasminogen taught by Robitaille. One would have been motivated to do so since Robitaille teaches administering a plasminogen to treat a plasminogen deficiency, and Li teaches a combination of Glu- and Lys- plasminogen can be used treat a plasminogen deficiency. Applicants are referred to In re Kerkoven (205 USPQ 1069) in which it was shown to be prima facia obvious to combine two compositions, each of which is taught by the prior art to be used for that very same purpose. Therefore, then, barring unexpected results, one would reasonably expect enhanced, additive, or synergistic activity to be observed by combining the compositions or materials. One would have had a reasonable expectation of success since Li teaches both forms of plasminogen can be used to treat a plasminogen deficiency. Therefore claim 38 is rendered obvious as claimed.
Robitaille suggests treating a patient with an acquired Glu-plasminogen deficiency (supra). Therefore the patient is at risk of developing the conditions recited in claims 39-40.
Robitaille teaches a plasminogen-deficient subject is defined as a subject that has a plasmatic plasminogen activity that is lower than the level of plasmatic plasminogen activity in a non-plasminogen-deficient normal subject (called “normal plasminogen activity”; hence, a control). The art teaches since there is variability in the plasminogen activity of a normal subject, the normal plasminogen activity is calculated in a pool collected from non-plasminogen-deficient subjects. It may be the mean or average (see page 9, lines 3-14). The reduced plasmatic plasminogen activity is less than or equal to about 70% of the normal plasminogen activity (page 22, line 29). Therefore claim 41 is included in this rejection.
The art measures plasminogen in patient blood (supra). The reduced plasmatic plasminogen activity is less than or equal to about 70% of the normal plasminogen activity (page 22, line 29). Therefore claim 44 is included in this rejection.
As set forth above, DIC comprises microthrombi of capillaries. Therefore claim 45 is included in this rejection.
As set forth above, the art teaches DIC may cause tissue ischemia from occlusive microthrombi (see page 18, first paragraph). Claim 48 recites “…the ischemic region would cause necrosis of at least a part of a tissue without administration of the Glu-plasminogen to the patient, and at least one thrombotic event”. This is interpreted to mean administration would cause necrosis and a thrombotic event in the absence of Glu-plasminogen. Because the art teaches a patient with a condition associated with an ischemic region (supra), it would be expected to cause necrosis and a thrombotic in the absence of Glu-plasminogen. Therefore claim 48 is included in this rejection.
Because the method of claim 31 is rendered obvious, it would prevent the thrombotic events recited in claims 49-52.
The dose recited in claim 53 is rendered obvious on the grounds set forth above claim 53.
As set forth above, Robitaille teaches Glu-plasminogen can be administered to prevent a thrombotic event. The art teaches Glu-plasminogen is known to have a half-life of about 2.2 days in normal non plasminogen-deficient subjects (page 24, lines 14-15). The plasmatic level of plasminogen activity will increase during a period called the 'accumulation period', which lasts generally up to 3 to 5 times the half-life of a compound in a subject's plasma. After that accumulation period, the plasminogen elimination and the plasminogen input comes to an equilibrium and the plasmatic level of plasminogen activity stops to increase and reaches a plateau, which is called the 'steady-state' (see Figure 4). During the steady-state, the trough level remains stable at a particular level (page 11, lines 10-15). The skilled artisan would administer Glu-plasminogen within one week of an event with a risk of developing a thrombotic event since to accumulate and achieve a steady state level of Glu-plasminogen in the subject’s plasma. Therefore claim 54 is included in this rejection.
Robitaille identifies surgery as a condition that represents an acquired plasminogen deficiency (see page 14, line 25). Therefore claim 55 is rendered obvious.
Robitaille teaches daily administration for at least 2 days in Figure 8A. The art teaches plasminogen can be administered intravenously (page 23, line 26). Therefore claim 56 is included in this rejection.
Example 1 discloses a patient with plasminogen deficiency (hence, inborn). The art teaches human adults and adolescents receive a dose of 2 mg/kg Glu-plasminogen by intravenous infusion. The disclosed dose reads on the amount recited in claim 58. The art teaches plasminogen antigen levels and activity is measured in blood samples following infusion (see page 26, lines 18-25). Examiner notes claim 58 requires dosing and measuring plasminogen in the patient’s blood. Therefore the art anticipates the required steps of claim 58.
Robitaille teaches DIC (supra). Therefore claim 59 is included in this rejection.
Robitaille teaches treating a Glu-plasminogen deficiency (supra). Therefore the patient is at risk of developing a thrombotic event as recited in claim 60.
Robitaille teaches the patient may have DIC (supra). Therefore claim 61 is included in this rejection.
Robitaille teaches multiple doses of plasminogen can be administered so as to build up a concentration of the desired level (see last sentence on page 10 bridging first lie of page 11). The art teaches the patients treated have a reduced plasminogen activity that is about 70% or less, about 60% or less, about 50% or less, about 40% or less, about 35% or less or about 30% or less (see page 22, lines 29-31). The skilled artisan would repeat treatment as long as the patient is at least 30% lower (hence, lower than 10%) than normal since the art teaches patients with this level of are treated by the disclosed method. Therefore claim 62 is rendered obvious.
Therefore Applicant’s Invention is rendered obvious as claimed.
RESPONSE TO APPLICANT’S ARGUMENTS
The arguments made in the response filed on 30 June 2026 are acknowledged.
Argument 1: The arguments state a broad range of a pharmaceutical composition containing plasminogen and not the claimed dose of Glu-plasminogen.
Response 1: Li teaches administering “plasminogen” to treat thrombus ([0001]). Li teaches a composition comprising plasminogen with an optional carrier ([0108]). Li teaches Glu-plasminogen can be administered. Li teaches a composition comprising plasminogen with an optional carrier ([0108]). While Li teaches a broad range, the art also teaches the “dose” of the composition containing plasminogen can include 0.02 mg/kg and 0.25 mg/kg ([0117]). The passage describes the dosage in terms of plasminogen. One of ordinary skill in the art would interpret the dose taught by Li as referring to the amount of plasminogen administered (the therapeutic). Li teaches
“natural plasminogen” (hence, Glu-plasminogen [0004]) has the advantage of easy adjustment of thrombolytic strength ([0009]). Therefore one of ordinary skill in the art would adjust the 0.05 mg/kg to a lower dose based on the desired thrombolytic strength. The Applicant has not provided evidence of criticality at the claimed range. The argument is not persuasive.
Argument 2: The Applicant argues Li teaches various conditions and does not teach Glu-plasminogen is preferred. The Applicant argues the rejection relies on impermissible hindsight reasoning.
Response 2: Robitaille is relied upon because it teaches administering Glu-plasminogen. Robitaille treats an acquired plasminogen deficiency. Li teaches plasminogen can be administered to treat an acquired deficiency. Li teaches Glu-plasminogen can be administered. The rejection relies upon the explicit teachings of the prior art. The argument is not persuasive.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NATALIE MOSS whose telephone number is (571) 270-7439. The examiner can normally be reached on Monday-Friday, 8am-5pm EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sharmila Landau can be reached on (571) 272-0614. The fax phone number for the organization where this application or proceeding is assigned is (571) 270-8439.
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/NATALIE M MOSS/ Examiner, Art Unit 1653
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