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 .
Applicant's Amendment/Request for Reconsideration-After Non-Final Rejection, filed 30 December 2025, has been entered and fully considered.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 9/30/2025 and 12/23/2025 are being considered by the examiner. Consequently, two corresponding 1449 forms are attached.
Status of Claims
Claims 1-28 are pending and are examined on the merits.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged. Priority of US application 62/894,694 filed 8/31/2019 is acknowledged.
Claim Rejections - 35 USC § 101
This rejection is maintained from the previous Office Action. Modifications are necessitated by claim amendments.
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 1-28 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter.
Step 1: Process, Machine, Manufacture or Composition
Claims 1-19 are directed to a process, here "a computer implemented method," for “providing a consistent particle concentration calculation”, with process steps like “analyzing,” “receiving,” “receiving,” and “executing.”
Claim 20 is directed to another process, here another "computer implemented method," for “providing a consistent particle concentration calculation”, with process steps like “analyzing,” “receiving,” and “executing.”
Claims 21-24 are directed to a third 101 process, here a third "computer implemented method," for “providing a consistent particle calculation”, with five process steps like “analyzing” and “executing”.
Claims 25-28 are directed to a fourth 101 process, here a fourth "computer implemented method," for “providing a consistent particle calculation”, with five process steps like “executing”.
Step 2A Prong One: Identification of an Abstract Idea
Claim 1 recites:
Determine a capsid protein mass of the sample, mA , and a modifier mass of the sample mB, with respect to an absorbance value, Aλ , collected by the at least two concentration detectors collected at a wavelength, λ.
----This step does not specify how exactly an absorbance value Aλ is analyzed that leads to determination of mA and mB. Under a broadest reasonable interpretation (BRI), this step recites the mathematical correlation between the measured light (absorbance value Aλ) and physical features (mA and mB). Therefore, this step equates to an abstract idea of mathematical concepts.
Determine a capsid protein molar mass of the sample, MA, based on refractive index increment values obtained from the at least one concentration detector.
----This step does not specify how exactly the refractive index increment values are derived from the at least one concentration detector and how then MA is acquired.
Under a BRI, this step recites the mathematical correlation between the measured light out of the concentration detector and a physical feature (MA). Therefore, this step equates to an abstract idea of mathematical concepts.
Execute a set of logical operations from the received capsid protein molar mass of the sample, MA and the injection volume of the sample, v, and the analyzed capsid protein mass of the sample, mA to quantify a total VGDV particle concentration of the sample, CA.
-----This step does not specify how exactly a CA is quantified from the received MA, v and mA. Under a BRI, “to quantify a total VGDV particle concentration of the sample, CA“ with three input parameters encompasses a mathematical calculation. Hence, this step equates to an abstract idea of mathematical concepts.
Claim 20 recites:
Determine a modifier mass of the sample, mB, a modifier molar mass of the sample, MB, and at least one UV extinction coefficient of the sample.
----This step does not specify how exactly mB, MB, and at least one UV extinction coefficient of the sample are determined. Under a BRI, this step recites the mathematical correlation between the mB, MB, and at least one UV extinction coefficient of the sample and “detector signals” (previous step in claim 20). Therefore, this step equates to an abstract idea of mathematical concepts.
Determine a capsid protein mass of the sample, rnA, and the modifier mass of the sample, mB, by an absorbance value, Aλ, collected from the sample by the at least two concentration detectors at a wavelength, λ, in response to an output of the at least one static light scattering instrument.
----This step does not specify how exactly an absorbance value Aλ is analyzed that leads to determination of mA and mB. Under a BRI, this step recites the mathematical correlation between the detectors at a wavelength λ (absorbance value Aλ) and physical features (mA and mB). Therefore, this step equates to an abstract idea of mathematical concepts.
Execute a set of logical operations calculating a capsid protein mass of the sample, mA, and a capsid protein molar mass of the sample, MA, with respect to at least one refractive-index increment value from the at least one concentration detector;
----This step does not specify how exactly a mA and MA are calculated from the refractive-index increment value. Under a BRI, this step encompasses a mathematical calculation. Hence, this step equates to an abstract idea of mathematical concepts.
Executing, by the computer system, a set of logical operations from the capsid protein mass of the sample, mA and the capsid protein molar mass of the sample, MA, to quantify a total VGDV particle concentration of the sample, CA..
-----This step does not specify how exactly a CA is quantified from the received MA and mA. Under a BRI, “to quantify a total VGDV particle concentration of the sample, CA“ with two input parameters encompasses a mathematical calculation. Hence, this step equates to an abstract idea of mathematical concepts.
Claim 21 recites:
Execute a set of logical operations calculating a mass fraction of a protein in the sample, XA, with respect to an ultra-violet absorbance value, Aλ1, collected by the at least two concentration detectors from the sample at a first wavelength, λ1, an ultra-violet absorbance value, Aλ2, collected by the at least two concentration detectors from the sample at a second wavelength, λ2, an extinction coefficient of the protein, εA λ1, at the first wavelength, λ1, an extinction coefficient of the protein, εA λ2, at the second wavelength, λ2, an extinction coefficient of a modifier in the sample, εB λ2, at the first wavelength, λ1, and an extinction coefficient of the modifier in the sample, εB λ2, at the second wavelength, λ2;
----This step recites mathematical calculations to acquire additional parameters explicitly, which is an abstract idea of mathematical concepts.
Execute a set of logical operations calculating an extinction coefficient of the sample at the first wavelength, εVGDV λ1, with respect to the mass fraction of the protein in the sample, XA, the extinction coefficient of the protein at the first wavelength, εA λ1, and the extinction coefficient of the modifier in the sample at the first wavelength, εB λ1;
----This step recites mathematical calculations to acquire additional parameters explicitly, which is an abstract idea of mathematical concepts.
Execute a set of logical operations calculating an extinction coefficient of the sample at the second wavelength, εVGDV λ2, with respect to the mass fraction of the protein in the sample, XA, the extinction coefficient of the protein at the second wavelength, εA λ2, and the extinction coefficient of the modifier in the sample at the second wavelength, εB λ2;
----This step recites mathematical calculations to acquire additional parameters explicitly, which is an abstract idea of mathematical concepts.
Execute a set of logical operations calculating a refractive index increment of the sample, (dn/dc)VGDV, with respect to the mass fraction of the protein in the sample, XA, a refractive index coefficient of the protein, (dn/dc)A, and a refractive index coefficient of the modifier in the sample, (dn/dc)B;
----This step recites mathematical calculations to acquire additional parameters explicitly, which is an abstract idea of mathematical concepts.
Execute a set of logical operations calculating a total mass of the protein, mA, and a total mass of the modifier, mB, with respect to an ultra-violet absorbance value, Aλ, collected from the sample at a wavelength, λ, the mass fraction of the protein in the sample, XA, an extinction coefficient of the protein, εA λ, at the wavelength, λ, an extinction coefficient of a modifier in the sample, εB λ, at the wavelength, λ, where the wavelength, λ, is one of the first wavelength, λ1, and the second wavelength, λ2;
----This step recites mathematical calculations to acquire additional parameters explicitly, which is an abstract idea of mathematical concepts.
Quantifying, by the computer system from the total mass of the protein, mA, a total VGDV particle concentration of the sample, CA.
-----This step does not specify how exactly a CA is quantified from the received mA. Under a BRI, quantifying a total VGDV particle concentration of the sample, CA with one input parameter encompasses a mathematical calculation. Hence, this step equates to an abstract idea of mathematical concepts.
Claim 25 recites:
Execute a set of logical operations calculating a mass fraction of a protein in the sample, XA, with respect to an ultra-violet absorbance value, Aλ, collected from the sample at a wavelength, λ, a refractive index coefficient of a modifier in the sample, (dn/dc)B, a differential refractive index of a solution containing the sample, dRI, an extinction coefficient of the modifier, εB λ, at the wavelength, λ, an extinction coefficient of the protein, εA λ, at the wavelength, λ, a refractive index coefficient of the protein, (dn/dc)A;
----This step recites mathematical calculations to acquire additional parameters explicitly, which is an abstract idea of mathematical concepts.
Execute a set of logical operations calculating an extinction coefficient of the sample at the wavelength, εVGDV λ, with respect to the mass fraction of the protein in the sample, XA, the extinction coefficient of the protein at the wavelength, εA λ, and the extinction coefficient of the modifier in the sample at the wavelength, εB λ;
----This step recites mathematical calculations to acquire additional parameters explicitly, which is an abstract idea of mathematical concepts.
Execute a set of logical operations calculating a refractive index increment of the sample, (dn/dc)VGDV, with respect to the mass fraction of the protein in the sample, XA, the refractive index coefficient of the protein, (dn/dc)A, and the refractive index coefficient of the modifier in the sample, (dn/dc)B;
----This step recites mathematical calculations to acquire additional parameters explicitly, which is an abstract idea of mathematical concepts.
Execute a set of logical operations calculating a total mass of the protein, mA, and a total mass of the modifier, mB, with respect to the differential refractive index of the solution containing the sample, dRI, the mass fraction of the protein in the sample, XA, the refractive index coefficient of the protein, (dn/dc)A, and the refractive index coefficient of the modifier in the sample, (dn/dc)B; and
----This step recites mathematical calculations to acquire additional parameters explicitly, which is an abstract idea of mathematical concepts.
Quantifying, by the computer system from the total mass of the protein, mA, a total VGDV particle concentration of the sample, CA.
-----This step does not specify how exactly a CA is quantified from the received mA. Under a BRI, quantifying a total VGDV particle concentration of the sample, CA with one input parameter encompasses a mathematical calculation. Hence, this step equates to an abstract idea of mathematical concepts.
Additionally, claims 15-16, 18-19, 22 and 26 also recite abstract ideas in the mathematical concept grouping. Hence, claims do recite abstract ideas of mathematical concepts. Because the steps are directed to judicial exceptions, the claims must therefore be examined further to determine whether the claims integrate the above-identified JEs into a practical application (MPEP 2106.04(d)).
Step 2A Prong Two: Consideration of Practical Application
The claims result in a process of executing a set of logical operations from the received capsid protein molar mass of the sample, MA and the injection volume of the sample, v, and the analyzed capsid protein mass of the sample, mA to quantify a total VGDV particle concentration of the sample, CA. This process reads on a mathematical calculation with three input parameters, or say, the claim takes existing data to generate new data. The claims do not recite any additional elements that integrate the abstract idea/judicial exception into a practical application.
This judicial exception is not integrated into a practical application because the claims do not meet any of the following criteria:
An additional element reflects an improvement in the functioning of a computer, or an improvement to other technology or technical field;
an additional element that applies or uses a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition;
an additional element implements a judicial exception with, or uses a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim;
an additional element effects a transformation or reduction of a particular article to a different state or thing; and
an additional element applies or uses the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological environment, such that the claim as a whole is more than
a drafting effort designed to monopolize the exception.
Step 2B: Consideration of Additional Elements and Significantly More
The claimed method also recites "additional elements" that are not limitations drawn to an abstract idea. The recited additional elements are drawn to:
A computer (claims 1, 20-21, 25);
analyzing a viral gene delivery vehicle (VGDV) sample on a set of analytical instruments (claims 1, 20-21 and 25);
separating, by a separation instrument of the set of analytical instruments, the VGDV sample into constituencies; (claims 1, 20-21 and 25);
measuring, by at least two concentration detectors and at least one static light scattering instrument of the set of analytical instruments, the constituencies of the separated sample (claims 1, 20-21 and 25);
receive by a receiver of the computer system an injection volume of the sample, v, from an injection volume data source (claim 1);
storing the capsid protein molar mass of the sample, MA, in the capsid protein molar mass data source (claim 2);
the at least one separation instrument comprises at least one of a size exclusion chromatography unit, a field flow fractionation unit, and an ion-exchange chromatography unit (claim 4);
the at least one static light scattering instrument comprises a multi-angle light scattering instrument (claim 5);
the at least two concentration detectors comprise a first ultra-violet absorbance detector at a first wavelength, λ1, and a second ultra-violet absorbance detector at a second wavelength, λ2 (claim 6);
the first wavelength, λ1, is 260 nm, and wherein the second wavelength, λ2, is 280 nm (claims 7, 9, 11, 23, 27);
the at least two concentration detectors comprise an ultra-violet absorbance detector at a wavelength, λ, and a differential refractive index detector (claim 8);
the at least two concentration detectors comprise an ultra-violet absorbance detector at a wavelength, λ, and a fluorescence detector (claim 10);
the at least two concentration detectors comprise a differential refractive index detector and a fluorescence detector (claim 12);
receiving, by the computer system, a molar mass of a full modifier inside a full VGDV sample, MFull, from a full modifier molar mass data source (claim 15);
executing, by the computer system, a set of logical operations analyzing the full VGDV sample on the set (claim 16);
storing the molar mass of the full modifier inside the full VGDV sample, MFull, in the full modifier molar mass data source (claim 16);
receiving an injection volume of the sample, v, from an injection volume data source (claim 20).
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the above listed are all well-known and routine spectrometry instruments used in the industry. Simply, the above additional elements can be divided into instruments (connected to a computer) and the data acquired (about a sample) by the instruments.
The claims do not include additional elements that are sufficient to amount of significantly more than the judicial exception because it is routine and conventional to perform the acts of separating samples into constituencies (claims 1, 20-21 and 25) and measuring the constituencies of the separated sample (claims 1, 20-21 and 25). Other elements of the method include a computer which is a recitation of generic computer structure that serves to perform generic computer functions that are well-understood, routine, and conventional activities previously known to the pertinent industry.
When the additional elements are combined as whole, they are still well-known and conventional. The following references demonstrate the conventionality of the additional elements in combination:
Wen, Jie, Tsutomu Arakawa, and John S. Philo. "Size-exclusion chromatography with on-line light-scattering, absorbance, and refractive index detectors for studying proteins and their interactions." Analytical biochemistry 240.2 (1996): 155-166. Previously cited.
Gimpl, Katharina, Jessica Klement, and Sandro Keller. "Characterizing protein/detergent complexes by triple-detection size-exclusion chromatography." Biological Procedures Online 18 (2016): 1-18. Previously cited.
Fekete, Szabolcs, et al. "Theory and practice of size exclusion chromatography for the analysis of protein aggregates." Journal of pharmaceutical and biomedical analysis 101 (2014): 161-173. Previously cited.
Folta-Stogniew, E., and K. Williams. "Determination of molecular masses of proteins in solution: Implementation of an HPLC size exclusion chromatography and laser light scattering service in a core laboratory." Journal of biomolecular techniques: JBT 10.2 (1999): 51. Previously cited.
These references demonstrated that size-exclusion chromatography with on-line light-scattering, UV absorbance, and refractive index detectors for studying proteins and their interactions, are well-known and routine. Because the instruments are commercially available. Meanwhile, Gimpl demonstrated the conventionality of using a modifier in sample measurement.
The instruments used, such as the separation instruments, static light scattering instruments, and concentration detectors are all conventional as they are commercially available.
Viewed as a whole, these additional claim element(s) do not provide meaningful limitation(s) to transform the abstract idea recited in the instantly presented claims into a patent eligible application of the abstract idea such that the claim(s) amounts to significantly more than the abstract idea itself.
Therefore, the 101 rejection is maintained.
Response to Applicant’s Argument
In the remarks filed 30 September 2025, Applicant argued (page 14, last para through page 16, 2nd para) that claims recite patent-eligible subject matter. Particularly “claims are not directed to abstract ideas but rather to a specific technological solution involving a coordinated use of separation instruments, concentration detectors, and static light scattering instruments, and a method for analyzing VGDV samples and calculating particle concentrations that solve a concrete problem in biotechnology manufacturing: inconsistent particle concentration measurements” (page 15, 2nd para) This argument refers to the Step 2A/Prong One or Prong two in the 101 analysis. The argument is not persuasive. The application of instruments cannot deny mathematical operations. The last step in claim 1 is directed to an abstract idea of mathematical concept because the step recites a step that requires a mathematical calculation with recited input parameters. The judicial exceptions (more specifically the mathematical calculations) are about VGDV particle concentration (claim 1, last step), but this has not been captured, or reflected in, or used by any additional elements. The identified additional elements are instruments (connected to a computer) and the data acquired (about a sample) by the instruments, which do not apply, capture, and reflect the mathematical operations. There is no integration at Step 2A/Prong two.
Applicants argue (Remarks, page 16, par. 1) that “the mathematical operations serve as components of a larger technological process for analyzing viral gene delivery vehicle samples, rather than abstract mathematical concepts performed in isolation. The mere presence of mathematical operations does not render claims abstract when those operations are applied to solve a specific technological problem.”
Applicants arguments are not persuasive. It is true Examples are available that claims with mathematical operations recited are still 101 eligible. However those happen only when additional elements exist to apply, to capture and to reflect the technical merits rooted in the mathematical operations. In the instant claims, the identified additional elements, such as the instruments (connected to a computer) and the data acquired (about a sample) by the instruments, do not satisfy these requirement. In Thales Visionix Inc. v. United States, the question is whether additional elements or the combination of additional elements are more than "apply it" or are not. In the instant claims there is no “apply it”.
In the remarks, Applicant argued (page 16, last para through page 18, 5th para) that claims recite are integrated into a practical application due to a technical improvement that “provides concrete technological improvements by enabling sample analysis in under 30 minutes, compared to conventional methods requiring 24 hours to several weeks.” This argument refers to the Step 2A/Prong two in the 101 analysis. The argument is not persuasive. The judicial exceptions (more specifically the mathematical calculations) are drawn to determining VGDV particle concentration (claim 1, last step), but this has not been captured, or reflected in, or used by any additional elements. There is no integration into a practical application at Step 2A/Prong two.
In the remarks, Applicant argued (page 18, last para through page 20, 1st para) that “claims recite a non-conventional arrangement of instruments working in a coordinated fashion.” This argument refers to the Step 2B in the 101 analysis. The argument is not persuasive. Physical instruments, including separation instruments, static light scattering (SLS) instruments, concentration detectors, and a generic computer system configured to control specific physical parameters are well-known and commercially used in the industry. For example, the following references demonstrated the conventionality of “separation instrument+ multiple detectors+ static light scattering” (emphasis added):
Wen, Jie, Tsutomu Arakawa, and John S. Philo. "Size-exclusion chromatography with on-line light-scattering, absorbance, and refractive index detectors for studying proteins and their interactions." Analytical biochemistry 240.2 (1996): 155-166. Previously cited.
Gimpl, Katharina, Jessica Klement, and Sandro Keller. "Characterizing protein/detergent complexes by triple-detection size-exclusion chromatography." Biological Procedures Online 18 (2016): 1-18. Previously cited.
Fekete, Szabolcs, et al. "Theory and practice of size exclusion chromatography for the analysis of protein aggregates." Journal of pharmaceutical and biomedical analysis 101 (2014): 161-173. Previously cited.
Folta-Stogniew, E., and K. Williams. "Determination of molecular masses of proteins in solution: Implementation of an HPLC size exclusion chromatography and laser light scattering service in a core laboratory." Journal of biomolecular techniques: JBT 10.2 (1999): 51. Previously cited.
These references demonstrated that size-exclusion chromatography with on-line light-scattering, UV absorbance, and refractive index detectors for studying proteins and their interactions, are well-known and routine. Because the instruments are commercially available. Meanwhile, Gimpl demonstrated the conventionality of using a modifier in sample measurement.
For the above reasons, the 101 rejection is maintained.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/GL/
Patent Examiner
Art Unit 1686
/Anna Skibinsky/
Primary Examiner, AU 1635
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