DETAILED ACTION
In application filed on 12/18/2023, Claims 1-5, 7, 10, 13-15 and 17 are pending. The claim set submitted on 07/11/2026 is considered because this is the most recent claim set with some preliminary amendments. Claims 1-5 and 7 are considered in the current office 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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/18/2023 and 07/11/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Election/Restrictions
Applicant's election with traverse of Claims 1-5 and 7 in the reply filed on 07/11/2026 is acknowledged. The traversal is on the ground(s) that:
The applicant believes that the technical features of "neonatal biliary atresia" and "the conjugated bilirubin is bilirubin in Group 1 make a contribution over the prior art, thus can be considered as special technical features.
The claims of Groups IV, VI, VII and VIII share the same special technical features as the claims of Group 1 and therefore possess unity between these claims. Moreover, the applicant believes that all the pending claims satisfy the circumstance stipulated in 37 CFR 1.475(b)(4), namely "A process and an apparatus or means specifically designed for carrying out the said process." Therefore, the applicant respectfully submits that the claims of Groups I, IV, VI, VII and Vill should be examined together without any undue burden being placed on the Examiner.
Accordingly, reconsideration and withdrawal of the restriction requirement are respectfully requested.
This is not found persuasive because:
Groups I-VIII lack unity of invention under 37 CFR 1.475 and PCT Rule 13.1 because even though the inventions of these groups require the technical feature of “bilirubin”, this technical feature is not a special technical feature as it does not make a contribution over the prior art in view of Ito et al. ("Serum bilirubin fractions in cholestatic pediatric patients: determination with Micronex high-performance liquid chromatography." Journal of pediatric surgery 30.4 (1995): 596-599, submitted in IDS 01/10/2024).
In view of Applicant’s argument that the applicant believes that the technical features of "neonatal biliary atresia" and" the conjugated bilirubin is bilirubin in Group 1 make a contribution over the prior art, thus can be considered as special technical features, Examiner submits that this technical feature is not a special technical feature as it does not make a contribution over the prior art in view of Ito et al. ("Serum bilirubin fractions in cholestatic pediatric patients: determination with Micronex high-performance liquid chromatography." Journal of pediatric surgery 30.4 (1995): 596-599, submitted in IDS 01/10/2024) in view of Suai et al. (JP2004180642A, Google machine translation used) (See Claim 1 rejection).
The requirement is still deemed proper and is therefore made FINAL.
Claim Objections
Claim 3 is objected to because of the following informalities:
Claim 3 recites “other indicators” in lines 4 of the Claim. It appears that this limitation should be recited as “any of the plurality of the other detection indicators”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
Claims 2-5 and 7 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 2 recites the limitation "preferably, the test subject…"; “more preferable, the blood sample…”; “such as a dried blood spot” in Claim 2.
It is not clear whether these limitations are required by the Claim.
Applicant should provide clarification.
For the purpose of expedited prosecution, the limitation "preferably, the test subject…"; “more preferable, the blood sample…”; “such as a dried blood spot” is interpreted by the Examiner as " the test subject…"; “the blood sample…”; “a dried blood spot”.
Moreover, Claims 3-5 are rejected by virtue of dependence on Claim 2.
Claim 4 recites the limitation "preferably, the organic solvent…".
It is not clear whether these limitations are required by the Claim.
Applicant should provide clarification.
For the purpose of expedited prosecution, the limitation "preferably, the organic solvent…" is interpreted by the Examiner as " the organic solvent…".
Moreover, Claim 5 is rejected by virtue of dependence on Claim 4.
Claim 5 recites the limitation "preferably, the weight ratio…"; “more preferably, the weight ratio…"; and “ further more preferably, the weight ratio…".
It is not clear whether these limitations are required by the Claim.
Applicant should provide clarification.
For the purpose of expedited prosecution, the limitation "preferably, the weight ratio…"; “ more preferably, the weight ratio…"; and “ further more preferably, the weight ratio…" is interpreted by the Examiner as " the weight ratio…"; “the weight ratio…"; and “ , the weight ratio…".
Claim 7 recites the limitation "preferably, the liquid chromatography…"; and “more preferably, the pH is …".
It is not clear whether these limitations are required by the Claim.
Applicant should provide clarification.
For the purpose of expedited prosecution, the limitation "preferably, the liquid chromatography…"; and “more preferably, the pH is …" is interpreted by the Examiner as ", the liquid chromatography…"; and “, the pH is …".
Claim 7 recites the limitation "the liquid chromatography tandem mass spectrometry and “the liquid chromatography" in lines 1-2; and “the pH” in line 12 There is insufficient antecedent basis for these limitations in the claim.
For the purpose of expedited prosecution, the limitation "the liquid chromatography tandem mass spectrometry “the liquid chromatography" and “the pH” is interpreted by the Examiner as "a method of liquid chromatography tandem mass spectrometry; “liquid chromatography" and “pH”.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 1-5 are rejected under 35 U.S.C. 103 as being unpatentable over by Ito et al. ("Serum bilirubin fractions in cholestatic pediatric patients: determination with Micronex high-performance liquid chromatography." Journal of pediatric surgery 30.4 (1995): 596-599, submitted in IDS 01/10/2024) in view of Suai et al. (JP2004180642A, Google machine translation used).
Regarding Claim 1, Ito teaches a method for assessing the risk of neonatal biliary atresia (See Abstract…The conjugated bilirubin (BDG + BMG) fraction in preoperative patients with biliary atresia (BA) was 48.8 -+ 5.1%, which was significantly higher than that in patients with infantile hepatitis (P < .01); See Page 596…neonates; thereby teaching “assessing the risk of neonatal biliary atresia”) , comprising a step of performing a quantitative detection of conjugated bilirubin (See Abstract… measurement of the conjugated bilirubin fraction …) as a biomarker (See Abstract; Page 596…The conjugated bilirubin (BDG + BMG) fraction in preoperative patients with biliary atresia (BA) was 48.8 -+ 5.1%, which was significantly higher than that in patients with infantile hepatitis (P < .01)) with a diagnostic device (See Abstract; Page 596… Bilirubin conjugates in the serum of cholestatic pediatric patients were investigated with Micronex high-performance liquid chromatography);
wherein the conjugated bilirubin (See Abstract; Page 596…The conjugated bilirubin (BDG + BMG) fraction) is bilirubin monoglucuronide (BMG), (See Page 596… bilirubin monoglucuronide (BMG)).
Ito does not teach that the conjugated bilirubin is bilirubin β-monoglucuronide.
In the analogous art of providing a selective method and reagent for accurately measuring bilirubin δ fraction in a biological sample using bilirubin oxidase, and the difference between the sum of δ bilirubin value and conjugated bilirubin value, and the total bilirubin value, Suai teaches that the conjugated bilirubin is bilirubin β-monoglucuronide (See Page 3… β: monoglucuronide bilirubin; See Page 9… monoglucuronide bilirubin (β)).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified a method of Ito to include that he conjugated bilirubin is bilirubin β-monoglucuronide, as taught by Suai for the benefit of of providing the analysis of reactivity of Reagent-1 and Reagent-2 for Various Bilirubins by HPLC (Suai, Page 9), allowing for the provision of a selective method and reagent for accurately measuring bilirubin δ fraction in a biological sample using bilirubin oxidase, and the difference between the sum of δ bilirubin value and conjugated bilirubin value, and the total bilirubin value (Suai, Abstract, Page 1).
Regarding Claim 2, the method of claim 1 is obvious over Ito in view of Suai.
Ito teaches that the diagnostic device (See Abstract; Page 596… Bilirubin conjugates in the serum of cholestatic pediatric patients were investigated with Micronex high-performance liquid chromatography) is selected from a medical device, a kit, a test strip and a detection device (See Abstract; Page 596… Bilirubin conjugates in the serum of cholestatic pediatric patients were investigated with Micronex high-performance liquid chromatography, thereby teaching “detection device”);
wherein the biological sample from a test subject is detected with the diagnostic device (See Abstract; Page 596… Bilirubin conjugates in the serum of cholestatic pediatric patients were investigated with Micromax high-performance liquid chromatography);
preferably, the test subject is a newborn (See Page 596…and the age of
neonates with jaundice was 19.4 _+ 12.6 days);
Examiner submits that the Claimed “and/or, the biological sample is a blood sample” is interpreted as optional, thus not required by the claim;
more preferably, the blood sample is selected from whole blood, plasma, serum and a dried blood spot, such as a dried blood spot (See Abstract…serum of cholestatic pediatric patients).
Regarding Claim 3, the method of claim 2 is obvious over Ito in view of Suai.
Ito teaches that, other detection indicator of the test subject can be optionally combined to assess the risk of neonatal biliary atresia with the diagnostic device (This limitation is interpreted as optional and thus not required by the claim), and the other detection indicator (See Page 596… persistent jaundice, thereby teaching “the other detection indicator”) is selected from one or more of free bilirubin, biliverdin, y-glutamyl transferase, MMP-7 and other indicators (See Page 596… persistent jaundice, thereby teaching “the other detection indicator”) capable of directly or indirectly diagnosing neonatal biliary atresia (See Abstract…The conjugated bilirubin (BDG + BMG) fraction in preoperative patients with biliary atresia (BA) was 48.8 -+ 5.1%, which was significantly higher than that in patients with infantile hepatitis (P < .01); See Page 596…neonates; thereby teaching “directly or indirectly diagnosing neonatal biliary atresia”).
Regarding Claim 4, the method of claim 2 is obvious over Ito in view of Suai.
Ito teaches that the biological sample (See Page 596…Serum samples) is contained in an organic solvent dispersion system (See 596…0.1 mol/L acetic acid-5 mmol/L pentane sulfonic acid: acetonitrile);
preferably, the organic solvent (See 596… acetonitrile) of the organic solvent dispersion system (See 596…0.1 mol/L acetic acid-5 mmol/L pentane sulfonic acid: acetonitrile) is selected from one or more of methanol, ethanol, acetone, propylene glycol, acetonitrile, and a combination thereof (See 596… acetonitrile);
Examiner submits that the limitation “and/or, the supernatant is collected for detection after the biological sample is centrifuged; and/or, the method for quantitative detection is liquid chromatography tandem mass spectrometry” are interpreted as optional, thus not required by the claim.
Regarding Claim 5, the method of claim 4 is obvious over Ito in view of Suai.
Regarding Claim 5, Ito teaches that the organic solvent dispersion system (See 596…0.1 mol/L acetic acid-5 mmol/L pentane sulfonic acid: acetonitrile) comprises a first stabilizer (See Page 596… 0.1mol/L acetic acid…) and a second stabilizer (See Page 596…5 mmol/L pentane sulfonic acid).
the weight ratio of the content (See Page 596…0.1 mol/L acetic acid…See Page 596… 5mmol/L pentane sulfonic acid has a weight ratio) of the first stabilizer (See Page 596… 0.1mol/L acetic acid…) and the second stabilizer (See Page 596…5 mmol/L pentane sulfonic acid) in the organic solvent dispersion system (See 596…0.1 mol/L acetic acid-5 mmol/L pentane sulfonic acid: acetonitrile);
preferably, the weight ratio of the content (See Page 596…0.1 mol/L acetic acid…See Page 596… 5mmol/L pentane sulfonic acid has a weight ratio) of the first stabilizer (See Page 596… 0.1mol/L acetic acid…) and the second stabilizer (See Page 596…5 mmol/L pentane sulfonic acid) in the organic solvent dispersion system (See 596…0.1 mol/L acetic acid-5 mmol/L pentane sulfonic acid: acetonitrile);
Examiner submits that the limitation “and/or, the first stabilizer is selected from one or more of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate (PG), tertiary butythydroquinone (TBHQ), and a combination thereof; the second stabilizer is ascorbic acid” is interpreted as optional and thus not required by the claim;
more preferably, the weight ratio of the content (See Page 596…0.1 mol/L acetic acid…See Page 596… 5mmol/L pentane sulfonic acid has a weight ratio) of the first stabilizer (See Page 596… 0.1mol/L acetic acid…) and the second stabilizer (See Page 596…5 mmol/L pentane sulfonic acid) in the organic solvent dispersion system (See 596…0.1 mol/L acetic acid-5 mmol/L pentane sulfonic acid: acetonitrile);
Examiner submits that the limitation “and/or, the first stabilizer is butylated hydroxytoluene (BHT) and the second stabilizer is ascorbic acid” is interpreted as optional and thus not required by the claim;
further more preferably, the weight ratio of the content (See Page 596…0.1 mol/L acetic acid…See Page 596… 5mmol/L pentane sulfonic acid has a weight ratio) of the first stabilizer (See Page 596… 0.1mol/L acetic acid…) and the second stabilizer (See Page 596…5 mmol/L pentane sulfonic acid) in the organic solvent dispersion system (See 596…0.1 mol/L acetic acid-5 mmol/L pentane sulfonic acid: acetonitrile).
Ito does not teach weight ratios in the ranges of 1:(1 to 50); 1:(10 to 45); of 1:(20 to 40); and of 1:(30 to 40).
However, MPEP § 2144.05, Part II, Subpart B holds that a particular parameter that is recognized as a result effective variable (“a variable that achieves a recognized result”) would be one, but not the only motivation for a person of ordinary skill in the art to experiment to reach another workable product or process. In the design of HPLC solvents for analyte separations, the selection of optimal experimental conditions including weight ratios or concentration of stabilizers (such as BHT) in HPLC solvents alters baseline stability, ghost peak formation, and detector interference depending on whether isocratic or gradient elution is used.
Thus, the weight ratios of contents of the first and second stabilizers in the ranges of 1:(1 to 50); 1:(10 to 45); of 1:(20 to 40); and of 1:(30 to 40), are a result effective variables.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to design an organic solvent dispersion system comprises a first stabilizer and a second stabilizer with weight ratios in the ranges of 1:(1 to 50); 1:(10 to 45); of 1:(20 to 40); and of 1:(30 to 40), for the benefit of performing the chromatographic separation of bilirubin (Page 596…Materials and Methods) which allows for the measurement of the conjugated bilirubin fraction enabled BA to be differentiated from infantile hepatitis, and the delta bilirubin fraction proved to be an important indicator of cholestasis in postoperative BA patients with normal serum bilirubin (Page Abstract, 596…Materials and Methods).
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Ito et al. ("Serum bilirubin fractions in cholestatic pediatric patients: determination with Micronex high-performance liquid chromatography." Journal of pediatric surgery 30.4 (1995): 596-599, submitted in IDS 01/10/2024) in view of Suai et al. (JP2004180642A, Google machine translation used) as applied to claim 1 above, and further in view of Chan et al. (US20120295883A1).
Regarding Claim 7, the method of claim 1 is obvious over Ito in view of Suai.
Ito teaches wherein, in the liquid chromatography tandem mass spectrometry (See Abstract, Page 596…Micronex high-performance liquid chromatography), the liquid chromatography (See Abstract, Page 596…Micronex high-performance liquid chromatography) is selected from high performance liquid chromatography, ultra high performance liquid chromatography and nanoliter liquid chromatography (See Abstract, Page 596…Micronex high-performance liquid chromatography, thereby teaching “high performance liquid chromatography”);
preferably, the liquid chromatography (See Abstract, Page 596…Micronex high-performance liquid chromatography) is high performance liquid chromatography (See Abstract, Page 596…Micronex high-performance liquid chromatography, thereby teaching “high performance liquid chromatography”), the column of the liquid chromatography (See Page 596…a Micronex RP-30 column (6 x 150 mm; Sekisui Chemical Co, Osaka, Japan), is selected from C8 and C18 silica gel-packed columns;
The limitations “and/or, the composition of the mobile phase of the liquid chromatography is: aqueous phase A, selected from ultrapure water with a pH of 3-4.5; organic phase B, selected from one or more of acetonitrile, ethanol, methanol, propylene glycol and isopropanol; and/or, the mass spectrometry is selected from quadrupole mass spectrometry, time-of-flight mass spectrometry, ion hydrazine mass spectrometry and high-resolution orbital hydrazine mass spectrometry” are interpreted as optional, thus not required by the Claim;
more preferably, the pH is adjusted by a pH adjuster, the pH adjuster is preferably selected from ammonium acetate-acetic acid, ammonium formate-formic acid, trifluoroacetic acid, and trichloroacetic acid buffer systems; more preferably the ammonium acetate-acetic acid buffer system;
The limitation “and/or, the organic phase B is selected from one or more of acetonitrile, methanol, and isopropanol; the organic phase B is preferably consisted of acetonitrile, methanol, and isopropanol; and/or, the condition and the mode settled for qualitative and quantitative detection of mass spectrometry comprise: selecting electrospray ion source (ESI) and selecting ion scan mode based on the response of a target compound to be detected; selecting a multiple reaction monitoring method (MRM) and setting parameters for the multiple reaction monitoring mode” are interpreted as optional and not required by the claim.
Ito does not teach:
the liquid chromatography tandem mass spectrometry;
the column of the liquid chromatography, is selected from C8 and C18 silica gel-packed columns; and
more preferably, the pH is adjusted by a pH adjuster, the pH adjuster is preferably selected from ammonium acetate-acetic acid, ammonium formate-formic acid, trifluoroacetic acid, and trichloroacetic acid buffer systems; more preferably the ammonium acetate-acetic acid buffer system.
In the analogous art of methods to therapeutic uses of pharmaceutical compositions comprising the substituted pyrazolopyridine compounds, for example, in cancer and neurodegenerative diseases, Chan teaches:
the liquid chromatography tandem mass spectrometry (See Para 0244… LC-MS was performed on an Agilent 1200 Series LC coupled to an Agilent 6140 quadrupole mass spectrometer);
the column of the liquid chromatography, is selected from C8 and C18 silica gel-packed columns (See Para 0244… an Agilent SD-C18 column; Examiner, under BRI, submits that an Agilent SD-C18 column is silica based); and
more preferably, the pH is adjusted by a pH adjuster (See Para 0246… 0.1% trifluoroacetic acid is added to the water (low pH buffer), …), the pH adjuster (See Para 0246… 0.1% trifluoroacetic acid) is preferably selected from ammonium acetate-acetic acid, ammonium formate-formic acid, trifluoroacetic acid, and trichloroacetic acid buffer systems; more preferably the ammonium acetate-acetic acid buffer system (See Para 0246… 0.1% trifluoroacetic acid is added to the water (low pH buffer), …thereby teaching “ trifluoroacetic acid”).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Ito to include: the liquid chromatography tandem mass spectrometry; the column of the liquid chromatography, is selected from C8 and C18 silica gel-packed columns; and more preferably, the pH is adjusted by a pH adjuster, the pH adjuster is preferably selected from ammonium acetate-acetic acid, ammonium formate-formic acid, trifluoroacetic acid, and trichloroacetic acid buffer systems; more preferably the ammonium acetate-acetic acid buffer system” as taught by Chan, for the benefit of providing LC-MS method for analysis of substituted pyrazolopyridine compounds (Chan, Para 0238-0246), allowing for the provision of compounds that are capable of inhibiting one or more kinases, more particularly, LRRK, even more preferably LRRK2 (Chan, Para 0006),
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to OYELEYE ALEXANDER ALABI whose telephone number is (571)272-1678. The examiner can normally be reached on M-F 7:30am-5:30pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lyle Alexander can be reached on (571) 272-1254. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/OYELEYE ALEXANDER ALABI/ Examiner, Art Unit 1797
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