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 OFFICE ACTION
This Office Action is in response to the papers filed on 08 January 2026.
CLAIMS UNDER EXAMINATION
Claims 31, 33-34, 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WITHDRAWN REJECTIONS
The rejection of claims 41, 44, 58, 62 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, has been withdrawn due to claim amendment.
REJECTIONS
New grounds of rejection have been necessitated by claim amendment.
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, 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 Kaufman et al. (Clinicopathological Correlations of Disseminated Intravascular Coagulation in Patients with Head Injury. Neurosurgery 15(1):p 34-42, July 1984) and Li et al. (Plasminogen For Use In Preventing Or Treating Acute Thrombosis and Chronic Thrombosis. EP3395359 published as WO2017/101866) as evidenced by as evidenced by Asakura et al. (previously cited; Classifying types of disseminated intravascular coagulation: clinical and animal models. Journal of Intensive Care 2014, 2:20) and Bosetti et al. (Small Blood Vessels: Big Health Problems?”: Scientific Recommendations of the National Institutes of Health Workshop. Journal of the American Heart Association. Volume 5, Number 11).
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).
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 the administration of an effective doses of plasminogen is for increasing the subject plasminogen activity level by at least 1% of the normal plasminogen activity and for maintaining the subject plasminogen activity level superior to said subject plasminogen activity level plus 1% of the normal plasminogen activity over a supplementation period (see page 8, lines 25-29).
Regarding the subject: Robitaille teaches the plasminogen-deficient subject of the present invention has “an acquired deficiency” (see Abstract; see page 2, number 5; page 8, line 17). As evidenced by instant claim 59, a subject with Disseminated intravascular coagulation (DIC) reads on claim 31.
Robitaille identifies Disseminated intravascular coagulation (DIC) as an acquired deficiency. Robitaille teaches DIC may cause tissue ischemia from occlusive microthrombi (see page 18, line 4). As evidenced by Asakura et al. “Disseminated intravascular coagulation (DIC) is a condition in which there is widespread and persistent activation of coagulation in the presence of underlying disease that causes diffuse microthrombi in small blood vessels”. As evidenced by the instant specification microthrombi are thrombotic events of small size of a diameter of less than 1 mm ([0019]). Therefore microthrombi less than 1mm in diameter would be present in a patient with DIC. As evidenced by the Journal of the American Heart Association (Bosetti) “small blood vessels” have an internal diameter of <100 µm (hence, less than 0.1 mm; first sentence of Introduction). As evidenced by Bosetti, arterioles, venules and capillaries are small vessels (page 1, right column, last paragraph). Therefore DIC is a condition that causes microthrombi in blood vessels with a diameter less than 0.5 mm.
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The deficiencies of Robitaille are:
The art is silent regarding the number of thrombotic events in blood vessels having diameters of less than 0.5 mm. Robitaille teaches administering at least 0.5 mg/kg body weight. The art does not teach 0.01 to 0.40 mg/kg body weight.
Kaufman et al. examine 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). Therefore Kaufman teaches human patients with DIC can have 10-100 microthrombi.
Li administers plasminogen to treat thrombosis in a subject ([0024]). The thrombosis is small or microvascular thrombosis ([0025]). The art treats a human ([0027]). Li treats a subject with a low level of plasminogen ([0028]). Li teaches administering Glu-plasminogen ([0035]). The art teaches the plasminogen can be administered at a dose of 0.02 mg/kg ([0017]). Li teaches the plasminogen thrombolytic rate can be controlled by the dose of plasminogen ([0018]). Li teaches Glu-plasminogen is the natural, secreted form of plasminogen ([0004]). The art teaches natural plasminogen has good function of dissolving thrombi with easy adjustment of thrombolytic strength ([0009]).
It would have been obvious to treat a subject with DIC using the method taught by Robitaille. One would have been motivated to do so since Robitaille identifies DIC as an acquired plasminogen deficiency that can be treated using the disclosed method. (See MPEP 2143 KSR “Rationale E. Obvious to Try” section). One would have had a reasonable expectation of success since Robitaille identifies DIC as an acquired deficiency which can be treated.
It would have been obvious to treat a subject with microthrombi of blood vessels less than 0.5 mm in diameter. One would have been motivated to do so since Robitaille teaches DIC can be treated with Glu-plasminogen, and DIC is a condition that causes microthrombi in small vessels with diameters less than 0.5 mm. It would have been obvious to try treating a subject with 10-100 microthrombi. Kauffman teaches DIC subjects with more than 10 microthrombi. One would have been motivated to administer Glu-plasminogen since Robitaille teaches DIC can be treated with Glu-plasminogen. One would have expected similar results since both references are directed to the same disorder.
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 Glu-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 I and 2144.05 II. 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.
Robitaille teaches administering a daily dose of at least 0.5 mg/kg of mass of the subject (supra). The dose taught by the art reads on 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.
The patient may have 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 08 January 2026 are acknowledged. The Applicant reiterates the arguments previously filed on 30 May 2025. The claims have been amended to require treating 10 to 100 thrombotic events.
Argument 1: The Applicant states “for the method of the present application, the use of proteolytically inactive Glu-plasminogen is essential in order to achieve the desired effect”. The Applicant states it is not clear whether the prior art administers Glu-plasminogen to patients.
Response 1: New grounds of rejection have been set forth above. Robitaille explicitly teaches administering Glu-plasminogen (see Abstract; see page 2 line 14; page 23, line 15). The art teaches the composition comprises “highly purified Glu-plasminogen” (see page 24, lines 16-17). Therefore the argument is not persuasive.
Argument 2: The Applicant argues Robitaille only mentions microthrombi in the context of DIC once, and does not mention blood vessel size. The Applicant states there is no standard definition for microthrombi.
Response 2: Robitaille identifies DIC as a condition that can be treated. Robitaille teaches DIC may cause tissue ischemia from occlusive microthrombi (see page 18, line 4). As evidenced by Asakura et al. “Disseminated intravascular coagulation (DIC) is a condition in which there is widespread and persistent activation of coagulation in the presence of underlying disease that causes diffuse microthrombi in small blood vessels”. As evidenced by the instant specification microthrombi are thrombotic events of small size of a diameter of less than 1 mm ([0019]). Therefore microthrombi less than 1mm in diameter would be present in a patient with DIC. As evidenced by the Journal of the American Heart Association (Bosetti) “small blood vessels” have an internal diameter of <100 µm (hence, less than 0.1 mm; first sentence of Introduction). As evidenced by Bosetti, arterioles, venules and capillaries are small vessels (page 1, right column, last paragraph). Therefore DIC is a condition that causes microthrombi in blood vessels with a diameter less than 0.5 mm. The post-filing reference cited by the Applicant (Chang et al.) does not explicitly define microthrombi, or teach a different diameter than that taught in the specification. Therefore the argument is not persuasive.
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 extension fee 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 date of this final action.
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) 273-8300.
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/NATALIE M MOSS/ Examiner, Art Unit 1653
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/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653