DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/11/2025 has been entered.
Claims 1, 3, 4, 6-9, 12-14 and 16-24 are pending in this application, Claims 3, 4, 6 and 16-20 are acknowledged as withdrawn, Claims 1, 7-9, 12-14 and 21-24 were examined on their merits.
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.
Claims 1, 7-9, 12-14 and 21-24 are rejected under 35 U.S.C. § 103 as being
unpatentable over Morikawa (US 2012/0064553 A1) in view of Wolff et al.(1996), as evidenced by Radomski et al. (1990), and Jianmongkol et al. (2000), all of record.
Morikawa discloses a blood coagulation time prolonging composition containing
thrombin as the blood coagulation activator (not mixed with a test sample) and a constituent comprising a guanidine-derived compound (see Paragraphs [0021]-[0024]).
Morikawa further discloses an alkylated guanidine having the structure
depicted in Formula I, wherein R1 represents a hydrogen, an amino group (e.g.
aminoguanidine), an alkyl (e.g. methylguanidine, ethylguanidine, benzylguanidine,
etc.) group, or an alkyl group with a substituent (see Paragraphs [0021]-[0022]), and
reading on Claims 1, 23 and 24.
Morikawa does not teach the mechanism by which the guanidine-derived
compound affects the blood coagulation prolonging time. Jianmongkol et al. evidences
that aminoguanidine is a metabolism-based inactivator of the three major isoforms of
nitric-oxide synthase (Pg. 13370, Abstract).
Regarding Claim 7, Morikawa teaches that the guanidine-derived compound
shown above may include an acid addition salt, such as a sulfate (see Paragraph
[0038]).
Regarding Claims 8 and 24, Morikawa teaches that the blood coagulation time prolonging agent of the present invention may be contained in the thrombin-containing reagent (that is, not mixed with the test sample) or contained in the specimen diluent (Pg. 3, Paragraph [0041]) and discloses when aminoguanidine is contained in the specimen diluent the concentration is 10-900 mM (overlapping the respective claimed ranges of 0.5 mM or greater or at least 20 mM) (Pg. 3, Paragraph [0043]). See the MPEP at 2144.05, I. It would have been obvious to those of ordinary skill in the art to modify the blood coagulation time prolonging composition containing thrombin as the blood coagulation activator (not mixed with a test sample) and a constituent comprising a guanidine-derived compound of Morikawa to utilize the guanidine derivative in the disclosed range because the reference teaches that this is a suitable concentration range of aminoguanidine when contained in a specimen diluent (not necessarily mixed with test sample).
Those of ordinary skill in the art would have been motivated to make this modification in order to obtain a the blood coagulation time prolonging composition with a suitable amount of guanidine derivative. There would have been a reasonable expectation of success in making this modification because Morikawa discloses a composition of thrombin and guanidine derivative (not mixed with a sample) as well as a suitable concentration range of guanidine when contained in a specimen diluent.
Regarding Claim 9, 12 and 13, Morikawa teaches the use of Good's buffers,
including MES, and teaches that the reagent may include preservatives or stabilizers
(see Paragraphs [0042] and [0053]). One of ordinary skill in the art would recognize
that the buffer solutions taught by Morikawa (Good's buffer, including MES) are
aqueous and will constitute a water-based composition. See Safety Data Sheet
provided for MES 1.0 M buffer solution showing water composition at 78.51 wt% and
water solubility. Therefore, it would be obvious to a skilled artisan that the reagent
comprising MES and preservatives taught by Morikawa is water-based/aqueous.
Regarding Claim 14, Morikawa teaches one or more component in the buffers,
preservatives or stabilizers that is a carboxylic derivative. Examples include acetate,
citrate, or propionic acid (see Paragraphs [0042] & [0053]).
Morikawa does not teach a reagent composition comprising a constituent comprising the claimed dialkylated guanidine compounds, as required by Claims 1, 21, 23 and 24;
wherein the composition comprises thrombin at a concentration of 20 U/mL or greater, as required by Claims 1, 23, and 24;
or wherein the constituent comprises two or more different guanidine derivatives, as required by Claim 22.
Wolff's general disclosure relates to the structural homologs of aminoguanidine to
clarify the relationship between their structure and both their mechanisms of inhibition
and isoform selectivity of nitric oxide synthase (see Abstract; and Pg. 228, Column 1,
Paragraph 1).
Wolff further teaches N,N-diaminoguanidine, methylguanidine, 1,1-
dimethylguanidine, and NG-Amino-L-arginine are structural homologs, and these
compounds inactivate nitric oxide synthase (NOS) isoforms (see Abstract; and Pg. 228,
Column 1, Paragraph 1). Additionally, Wolff teaches that the nNOS isoform plays
important role in platelet function (Pg. 227, Column 2, Paragraph 1).
As evidenced by Radomski, inhibitors of nitric oxide reduce platelet aggregation (Pg. 5193, Abstract) and further support the connection between the nitric oxide pathway and platelet function and aggregation.
It would have been obvious to one of ordinary skill in the art before the effective
filing date of the claimed invention to substitute the aminoguanidine/alkylguanidine
compounds taught by Morikawa for the close structural homologs taught by Wolff
because the compounds close structural similarities would be expected to function in the same way. See the MPEP at 2144.09, I. The ordinary artisan would have been motivated to make this substitution because, given the teachings of Wolff, the ordinary artisan would recognize that guanidine derivatives, including methylguanidine, 1,1-
dimethylguanidine, 1,1-diethylguanidine, and N-benzyl-N- methylguanidine, are
structural homologs possessing the ability to inhibit NOS isoforms, wherein NOS and
nitric oxide plays an important role in platelet aggregation. Morikawa teaches the use of
methylguanidine, ethylguanidine, benzylguanidine and aminoguanidine (structural
homologs) as substances for prolonging the coagulation time to adjust the coagulation
time to a desired time (see Paragraphs [0011] and [0021]-[0022]). Therefore, the
ordinary artisan would select structural homologs such as those listed above to prolong
coagulation time, since Wolff and Radomski teach the importance of nitric oxide for
platelet aggregation, Wolff teaches methylguanidine and 1,1-dimethylguanidine as
concentration-dependent inhibitors for NOS, and Morikawa teaches the use of
guanidine derivatives for prolonging coagulation time.
It would have been further obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the blood coagulation time prolonging composition of Morikawa and Wolff comprising thrombin and a constituent comprising a dialkylated guanidine compound to include thrombin in the composition at the claimed concentration of about 20 U/mL or greater because while the references listed above do not specifically teach the concentration limitation, one of ordinary skill in the art would recognize that the concentration of thrombin in a blood coagulation prolonging composition is a result-effective optimizable variable. Morikawa et al. teaches that thrombin functions as a blood coagulation activator. This is motivation for someone of ordinary skill in the art to practice or test the thrombin values widely to find those that are functional or optimal to sufficiently activate blood coagulation which then would be inclusive or cover the instantly claimed values. Absent any teaching of criticality by the Applicant concerning the concentration of thrombin in the composition, it would be prima facie obvious that one of ordinary skill in the art would recognize this limitation as an optimizable variable which can be met as a matter of routine optimization (see MPEP § 2144.05 (II)(B). Those of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to make this modification in order to obtain a blood coagulation prolonging composition containing a sufficient amount of blood coagulation activator. There would have been a reasonable expectation of success in making these modifications because all of the references are reasonably drawn to the same field of endeavor, that is, blood coagulation pronging using guanidine derivatives and structural homologs thereof.
It would have been further obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the blood coagulation time prolonging composition of Morikawa and Wolff comprising thrombin and a constituent comprising a dialkylated guanidine compound to include two or more different dialkylated guanidine compounds in the composition because the mere duplication of parts is not patentably significant unless a new or unexpected result is produced. See the MPEP at 2144.04, VI., B. Those of ordinary skill in the art would have been motivated to make this modification in order to obtain a blood coagulation prolonging constituent with different coagulation prolonging agents with potentially different characteristics and properties. There would have been a reasonable expectation of success in making this modification because Morikawa discloses a blood coagulation prolonging constituent containing a guanidine derivative, as well as disclosing alternative guanidine derivatives.
Claims 1, 7-9, 12-14 and 21-24 are rejected under 35 U.S.C. § 103 as being
unpatentable over Morikawa (US 2012/0064553 A1) in view of Wolff et al.(1996),
Monroe (US 2013/0183655 A1), as evidenced by Radomski et al. (1990), and as
evidenced by Jianmongkol et al. (2000), all of record.
Morikawa discloses a blood coagulation time prolonging composition containing
thrombin as the blood coagulation activator and a constituent comprising a guanidine-derived compound (see Paragraphs [0021]-[0024]).
Morikawa further discloses an alkylated guanidine having the structure
depicted in Formula I, wherein R1 represents a hydrogen, an amino group (e.g.
aminoguanidine), an alkyl (e.g. methylguanidine, ethylguanidine, benzylguanidine,
etc.) group, or an alkyl group with a substituent (see Paragraphs [0021]-[0022]), and
reading on Claims 1, 23 and 24.
Morikawa does not teach the mechanism by which the guanidine-derived
compound affects the blood coagulation prolonging time. Jianmongkol et al. evidences
that aminoguanidine is a metabolism-based inactivator of the three major isoforms of
nitric-oxide synthase (Pg. 13370, Abstract).
Regarding Claim 7, Morikawa teaches that the guanidine-derived compound
shown above may include an acid addition salt such as a sulfate (see Paragraph
[0038]).
Regarding Claims 8 and 24, Morikawa teaches that the blood coagulation time prolonging agent of the present invention may be contained in the thrombin-containing reagent (that is, not mixed with the test sample) or contained in the specimen diluent (Pg. 3, Paragraph [0041]) and discloses when aminoguanidine is contained in the specimen diluent the concentration is 10-900 mM (overlapping the respective claimed ranges of 0.5 mM or greater or at least 20 mM) (Pg. 3, Paragraph [0043]). See the MPEP at 2144.05, I.
It would have been obvious to those of ordinary skill in the art to modify the blood coagulation time prolonging composition containing thrombin as the blood coagulation activator (not mixed with a test sample) and a constituent comprising a guanidine-derived compound of Morikawa to utilize the guanidine derivative in the disclosed range because the reference teaches that this is a suitable concentration range of aminoguanidine when contained in a specimen diluent (not necessarily mixed with test sample). Those of ordinary skill in the art would have been motivated to make this modification in order to obtain a the blood coagulation time prolonging composition with a suitable amount of guanidine derivative. There would have been a reasonable expectation of success in making this modification because Morikawa discloses a composition of thrombin and guanidine derivative (not mixed with a sample) as well as a suitable concentration range of guanidine when contained in a specimen diluent.
Regarding Claim 9, 12 and 13, Morikawa teaches the use of Good's buffers,
including MES, and teaches that the reagent may include preservatives or stabilizers
(see Paragraphs [0042] and [0053]). One of ordinary skill in the art would recognize
that the buffer solutions taught by Morikawa (Good's buffer, including MES) are
aqueous and will constitute for a water-based composition. See Safety Data Sheet
provided for MES 1.0 M buffer solution showing water composition at 78.51 wt% and
water solubility. Therefore, it would be obvious to a skilled artisan that the reagent
comprising MES and preservatives taught by Morikawa is water-based/aqueous.
Regarding Claim 14, Morikawa teaches one or more component in the buffers,
preservatives or stabilizers that is a carboxylic derivative. Examples include acetate,
citrate, or propionic acid (see Paragraphs [0042] & [0053]).
Morikawa does not teach a reagent composition comprising a constituent comprising the claimed dialkylated guanidine compounds, as required by Claims 1, 21, 23 and 24;
wherein the composition comprises thrombin at a concentration of 20 U/mL or greater that is not mixed with the test sample, as required by Claims 1, 23, and 24;
or wherein the constituent comprises two or more different guanidine derivatives, as required by Claim 22.
Wolff's general disclosure relates to the structural homologs of aminoguanidine to
clarify the relationship between their structure and both their mechanisms of inhibition
and isoform selectivity of nitric oxide synthase (see Abstract; and Pg. 228, Column 1,
Paragraph 1).
Wolff further teaches N,N-diaminoguanidine, methylguanidine, 1,1-
dimethylguanidine, and NG-Amino-L-arginine are structural homologs, and these
compounds inactivate nitric oxide synthase (NOS) isoforms (see Abstract; and Pg. 228,
Column 1, Paragraph 1). Additionally, Wolff teaches that the nNOS isoform plays
important role in platelet function (Pg. 227, Column 2, Paragraph 1).
As evidenced by Radomski, inhibitors of nitric oxide reduce platelet aggregation (Pg. 5193, Abstract) and further support the connection between the nitric oxide pathway and platelet function and aggregation.
Monroe's general disclosure relates to a device or kit containing thrombin and a
coagulation controlling agent for stabilizing thrombin or accelerating its activity in a
blood sample (see Abstract).
Regarding Claims 1, 23, and 24, Monroe teaches the concentration of thrombin
used ranges from 0.1 to about 200 units (U) per milliliter of blood volume or from about 1 to about 20 U/mL blood volume (see Pgs. 3-4, Paragraph [0046]);
further discloses an embodiment wherein the thrombin is combined with the coagulation controlling agent that is not mixed with a test sample (Pg. 5, Paragraph [0063]);
and wherein blood tubes are prepared containing 1250 U/mL thrombin (overlapping the claimed concentration of 20 U/mL or greater) and coagulation controlling agent (Pg. 7, Paragraphs [0082]-[0083]) that are not mixed with blood. Therefore, Monroe teaches a concentration that overlaps with the claimed range of 20 U/mL or greater. It is noted that where the claimed ranges "overlap or lie inside the ranges disclosed by the prior art" and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists. See MPEP at 2144.05, I).
Further, Morikawa teaches thrombin for use in blood coagulability test/assay,
wherein a blood coagulation time prolonging agent (e.g., guanidine derivatives) can be
applied to any test including measuring a time from the initiation of coagulation by
mixing a reagent containing a blood coagulation activator and the like with a patient
specimen to the final conversion of fibrinogen into fibrin to be deposited (see Morikawa
at Paragraph. [0040]); Monroe similarly teaches a device or kit comprising thrombin and
coagulation controlling agent to stabilize thrombin/control coagulation in a blood sample
(see Abstract). Therefore, an ordinary artisan would have reasonable expectation of
success in modifying the blood coagulation assay/test of Morikawa to include features,
such as the concentration of thrombin used, of the similar kit/device of Monroe.
It would have been obvious to one of ordinary skill in the art before the effective
filing date of the claimed invention to substitute the aminoguanidine/alkylguanidine
compounds taught by Morikawa for the close structural homologs taught by Wolff
because the compounds close structural similarities would be expected to function in the same way. See the MPEP at 2144.09, I. The ordinary artisan would have been motivated to make this substitution because, given the teachings of Wolff, the ordinary artisan would recognize that guanidine derivatives, including methylguanidine, 1,1-
dimethylguanidine, 1,1-diethylguanidine, and N-benzyl-N- methylguanidine, are
structural homologs possessing the ability to inhibit NOS isoforms, wherein NOS and
nitric oxide plays an important role in platelet aggregation.
Morikawa teaches the use of methylguanidine, ethylguanidine, benzylguanidine and aminoguanidine (structural homologs) as substances for prolonging the coagulation time to adjust the coagulation time to a desired time (see Paragraphs [0011] and [0021]-[0022]). Therefore, the ordinary artisan would select structural homologs such as those listed above to prolong coagulation time, since Wolff and Radomski teach the importance of nitric oxide for platelet aggregation, Wolff teaches methylguanidine and 1,1-dimethylguanidine as concentration-dependent inhibitors for NOS, and Morikawa teaches the use of guanidine derivatives for prolonging coagulation time. Therefore, absent any unexpected results, the guanidine derivatives of Claims 1, 23, and 24 would be obvious alternatives to Morikawa's compounds. Modifications to Morikawa would be considered to be expected variants as provided by the teachings of Wolff. Accordingly, both the claimed invention and the prior art references, as a whole, would have been prima facie obvious to one of ordinary skill in the art at the time of filing. The ordinary artisan would have reasonable expectation of success in modifying the prior art reference to arrive at the claimed invention based on the above reasoning.
It would have been further obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the blood coagulation time prolonging composition of Morikawa and Wolff comprising thrombin and a constituent comprising a dialkylated guanidine compound to include two or more different dialkylated guanidine compounds in the composition because the mere duplication of parts is not patentably significant unless a new or unexpected result is produced. See the MPEP at 2144.04, VI., B.
Those of ordinary skill in the art would have been motivated to make this modification in order to obtain a coagulation prolonging constituent with different coagulation prolonging agents with potentially different characteristics and properties. There would have been a reasonable expectation of success in making this modification because Morikawa discloses a blood coagulation prolonging constituent containing a guanidine derivative, as well as disclosing alternative guanidine derivatives.
Response to Arguments
Applicant's arguments filed 12/11/2025 have been fully considered but they are not persuasive.
The Applicant argues that Monroe refers to thrombin concentrations are not a reagent not mixed with a test sample but are concentrations within a mixture containing a test sample (Remarks, Pg. 9, Lines 13-20).
This is not found to be persuasive for the following reasons, initially the Examiner notes the new rejection above which does not use Monroe as a reference. Secondly, the Examiner notes the new rejection above wherein Monroe teaches the concentration of thrombin used ranges from 0.1 to about 200 units (U) per milliliter of blood volume or from about 1 to about 20 U/mL blood volume (see Pgs. 3-4, Paragraph [0046]); further discloses an embodiment wherein the thrombin is combined with the coagulation controlling agent that is not mixed with a test sample (Pg. 5, Paragraph [0063]);
and wherein blood tubes are prepared containing 1250 U/mL thrombin (overlapping the claimed concentration of 20 U/mL or greater) and coagulation controlling agent without any test sample (Pg. 7, Paragraphs [0082]-[0083]). Therefore, Monroe teaches a composition comprising thrombin in a concentration that overlaps with the claimed range of 20 U/mL or greater not mixed with a test sample as claimed.
The Applicant argues that Morikawa allegedly only describes aminoguanidine concentration in a mixed solution of specimen, specimen diluent and thrombin containing reagent and does not disclose aminoguanidine in a reagent comprising thrombin and not mixed with a test sample as claimed (Remarks, Pg. 10, Lines 25-28).
This is not found to be persuasive for the following reasons, the Examiner notes the above new rejections wherein Morikawa discloses a blood coagulation time prolonging composition containing thrombin as the blood coagulation activator (not mixed with a test sample) and a constituent comprising a guanidine-derived compound (see Paragraphs [0021]-[0024]).
The Applicant argues that guanidine derivative concentrations above 20 mM in the reagent achieved thrombin stability for the temperature and time range considered, which the Examiner assumes is an allegation of unexpected results not suggested by the prior art (Remarks, Pg. 10, Lines 29-31 and Pg. 11, Lines 1-20).
This is not found to be persuasive for the following reasons, initially the Examiner notes that the alleged unexpected results are not commensurate in scope with the claimed invention being drawn to a particular guanidine derivative (dimethylguanidine/DMG), a thrombin concentration of 7 U/mL (which is below the claimed 20 U/mL or greater) as well as a particular buffer (MES), ph (6.3) and various concentrations of DMG (not found in the broad Claims 1 and 23). Secondly, the Examiner notes that Morikawa teaches that the blood coagulation time prolonging agent of the present invention may be contained in the thrombin-containing reagent (that is, not mixed with the test sample) or contained in the specimen diluent (Pg. 3, Paragraph [0041]) and discloses when aminoguanidine is contained in the specimen diluent the concentration is 10-900 mM (overlapping the claimed ranges of 0.5 mM or greater or at least 20 mM) (Pg. 3, Paragraph [0043]). Thus, the ordinary artisan looking for a suitable concentration of guanidine compound in a composition containing thrombin and not mixed with a test sample would look to the concentration of guanidine compound in the similar diluent composition which is also not necessarily mixed with a test sample.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to PAUL C MARTIN whose telephone number is (571)272-3348. The Examiner can normally be reached Monday-Friday 12pm-8pm EST.
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If attempts to reach the Examiner by telephone are unsuccessful, the Examiner’s supervisor, Sharmila G Landau can be reached at (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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/PAUL C MARTIN/Examiner, Art Unit 1653 01/05/2026