DETAILED CORRESPONDENCE
Status of the Application
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-5, 7-9 and 11-12 are pending in this application.
Applicant’s amendment to the claims filed 02/17/2026 is acknowledged. This listing of the claims replaces all prior versions and listings of the claims.
Applicant’s remarks filed on 02/17/2026 in response to the non-final rejection mailed on 11/14/2025 are acknowledged and have been fully considered.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Rejections - 35 USC § 112(b)
Claims 1-5, 7-9 and 11-12 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
The instant rejection is maintained from a previous office action, and any newly recited portions are necessitated by claim amendment.
Claim 1 (claims 2-5, 7-9 and 11-12 dependent therefrom) is indefinite for the phrases “method for monitoring changes in health status of an individual animal over time” in the preamble, “thereby monitoring changes in health status of the individual animal over time” at the end of step (4), and “repeatedly adding a test sample containing a microbiota derived from the individual animal over time to a plurality of probe solutions” in step (2). The limitation in step (2) is considered to describe a single test sample. As claim 1 does not actively recite steps to obtain multiple samples over time from the animal, the method of the claim encompasses the repeated analysis of a single sample derived from the individual animal, wherein the analyses of the single sample occurs at different times. In view of this broad yet reasonable interpretation, it is unclear how the analysis of a single sample derived from an individual animal can equate to monitoring changes in health status of the individual animal over time.
Response to Remarks: beginning on page 4 of Applicant’s response to rejections under 35 USC 112(b); Applicant in summary contends the amendments to the claims obviate the rejection under 112(b).
Applicant’s response is considered and found not convincing, as the amended limitation in step (2) of “repeatedly adding a test sample containing a microbiota derived from the individual animal over time to a plurality of probe solutions” is considered to recite the repeated addition of a single test sample to analysis at different times in order to monitor changes in the health status of an animal over time. For this reason, the amendments do not overcome the rejection of record.
Claim Rejections - 35 USC § 112(a)
Claim interpretation: The claims are drawn to a method for monitoring changes in health status of an animal over time comprising dissolving a probe capable of non-specifically interacting with two or more microorganisms in a plurality of solvents, repeatedly adding a test sample containing a microbiota derived from the animal over time to the probe solution, measuring fluorescence intensity of the probe solution, and analyzing the pattern of fluorescence, wherein the probe comprises a cationic polymer comprising at least five primary amino groups in one molecule having a weight-average MW of 1,000 – 500,000 and an environment-sensitive fluorophore covalently bound to 1-50% of the primary amino groups in the cationic polymer. The term “microorganism” is a broad term in the art which encompasses bacteria, fungi, archaea and protozoa, and as the instant specification at [para 0038] suggests the "microorganisms" that the probe targets may be any microorganism in any class, such as a bacterium, fungus, protozoan, or virus, and may be a mixture of microorganisms in a plurality of classes thereof, the claimed method encompasses the non-specific interaction of all probes comprising a cationic polymer comprising at least five primary amino groups in one molecule having a weight-average MW of 1,000 – 500,000 and an environment-sensitive fluorophore covalently bound to 1-50% of the primary amino groups in the cationic polymer with all microorganisms.
A. Claims 1-5, 7-9 and 11-12 are rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor at the time the application was filed, had possession of the claimed invention.
The instant rejection is maintained from a previous office action, and any newly recited portions are necessitated by claim amendment.
MPEP § 2163.II.A.3.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention”.
For claims drawn to a genus, MPEP § 2163.II.A.3.(a).ii) states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
According to § MPEP 2163.II.A.3.(a).ii), “[s]atisfactory disclosure of a ‘representative number’ depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus…Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are ‘representative of the full variety or scope of the genus,’ or by the establishment of ‘a reasonable structure-function correlation.’”
The factors considered in the Written Description requirement are (1) level of skill and knowledge in the art, (2) partial structure, (3) physical and/or chemical properties, (4) functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the (5) method of making the claimed invention. According to MPEP § 2163, “Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient."
The claims recite (in relevant part) a method of non-specifically interacting a genus of probes with a genus of microorganisms. With the exception of the probes containing at least five primary amino groups in one molecule having a weight-average MW of 1,000 – 500,000 and an environment-sensitive fluorophore covalently bound to 1-50% of the primary amino groups in the cationic polymer, the remaining structures of the genus of probes are unlimited. In this case, the genus of probes encompasses species that are considered widely variant with respect to structure. As the claims provide no structure to define the genus of microorganisms, the genus of microorganisms also encompasses species that are considered widely variant with respect to structure.
The specification discloses the following working examples of the method of non-specifically interacting the recited probe and microbiota samples comprising microorganisms:
The use of probes 1-12 according to Example 2 [specification para 0076] for the discrimination among bacterial isolates listed in Table 1 [specification para 0077], and the use of probes 1, 3, 6-8 and 11 for the discrimination of microbiota samples according to Examples 5-7 [specification beginning at para 0087].
As noted above, other than recited molecular weight range, a cationic polymer with the occurrence of at least five amine groups and a fluorophore, the claimed probe is otherwise structurally unlimited. Additionally, the "microorganism" as claimed to non-specifically interact with the probe in the method encompasses all microorganisms of bacteria, fungi, protozoa, archaea and virus.
Silhavy et al. (Cold Spring Harb Perspect Biol, 2010, 2:a000414; cited on the IDS filed 08/04/2025) reviews the bacterial cell envelope [title] and discusses the diversity of the architecture and components the cell envelope of Gram-positive and Gram-negative, which represent two types of bacterial morphology. Silhavy discusses the two types of morphology comprise a different outer surfaces, such as Gram-negative bacteria having an outer membrane that Gram-positive bacteria lack [p 2, col 2, final paragraph], and shows the structural diversity in cell envelope components between the two types of bacteria [Figure 3]. As not all bacteria can be classified into Gram-positive and Gram-negative types, one of skill in the art would recognize in view of Silhavy that cell structure varies among bacteria, and furthermore the cell structure among all microorganisms including fungi, protozoa, archaea, virus and bacteria is considered widely variant.
National Institute of Advanced Industrial Science and Technology et al. (WO 2018/088510 A1; cited on the IDS submitted 12/02/2021; reference is made to a machine translation cited on the Form PTO-892 mailed 08/05/2024; herein NIAIST) discloses cross-reactive sensing method for analyzing a protein-containing sample comprising dissolving a probe capable of non-specifically interacting with a plurality of proteins, wherein the probe comprises a cationic polymer comprising at least five primary amino groups in one molecule and having a weight average molecular weight of 1,000 to 500,000 and an environment-sensitive fluorophore covalently bonded to a part of the primary amino group in the cationic polymer [claim 1], wherein the fluorophore is bound to preferably 1-50% of the primary amino groups of the cationic polymer [p 4, para 13]. The method of NIAIST involves non-specifically interacting the probe in the analysis sample with protein [claim 1]. As the method of NIAIST relates to the non-specific interaction of probes with proteins associated with microorganisms, but without protein extraction steps, the proteins detected by the method of NIAIST are considered to include proteins present on the surface of the microorganisms, and therefore the method is interpreted to encompass the non-specific interaction of probes with microorganisms.
However, Applicant’s Declaration under 37 CFR 1.132 states in response to the disclosure of NIAIST at [para 7] that protein cross-reactive probes cannot access proteins in Gram-negative bacteria due to their outer membrane architecture, and that even if such probes could access surface proteins, their amount and variety would be too limited, and therefore one of skill in the art would not attempt to apply protein cross-reactive probes to microbiota.
While the probe of NIAIST is encompassed by the structural limitations of the probe set forth in the claims, Applicant’s Declaration asserts the probe of NIAIST would not function in the claimed method, as surface protein information is insufficient for such characterizations given the inaccessibility of proteins on the cell surface of Gram-negative bacteria, and therefore one of skill in the art would understand that protein-cross reactive probes cannot access proteins of these microorganisms. In accordance with the statements of Applicant’s Declaration, one of skill in the art would have recognized a high level of unpredictability that all probes comprising a cationic polymer with at least five primary amino groups in one molecule having a weight-average MW of 1,000 – 500,000 and an environment-sensitive fluorophore covalently bound to 1-50% of the primary amino groups in the cationic polymer are capable of non-specifically interacting with a microorganism as encompassed by the claims to maintain the desired activity/utility.
In view of the high level of unpredictability in the art of non-specifically interacting all probes with all microorganisms, because the genus of probes and the genus of microorganisms are widely variant with respect to structure, and the specification discloses the actual reduction to practice of interacting only 12 representative species of probes among a widely variant genus, and 16 representative species of microorganisms among a widely variant genus, one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus of probes and the genus of microorganisms, and thus, that the applicant was not in possession of the recited genus of probes and the genus of microorganisms. The claimed subject matter is not supported by an adequate written description because a representative number of species has not been described.
B. Claims 1-5, 7-9 and 11-12 are rejected under 35 U.S.C. 112(a) because the specification, while being enabling for the use of probes 1-12 according to Example 2 [specification para 0076] for the discrimination among bacterial isolates listed in Table 1 [specification para 0077], and the use of probes 1, 3, 6-8 and 11 for the discrimination of microbiota samples according to Example 5 [specification para 0087], does not reasonably provide enablement for all probes comprising a cationic polymer with at least five primary amino groups in one molecule having a weight-average MW of 1,000 – 500,000 and an environment-sensitive fluorophore and all microorganisms as encompassed by the claims. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
The instant rejection is maintained from a previous office action, and any newly recited portions are necessitated by claim amendment.
“The test of enablement is not whether any experimentation is necessary, but whether, if experimentation is necessary, it is undue.” In re Angstadt, 537 F.2d 498, 504, 190 USPQ 214, 219 (CCPA 1976). Factors to be considered in determining whether undue experimentation is required are summarized in In re Wands (858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)) as follows: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. See MPEP § 2164.01(a). The Factors considered to be most relevant to the instant rejection are addressed in detail below.
The nature of the invention: According to the specification at in para 0003-0004 “Indigenous microbiota are presently analyzed by phylogenetic systematics based on the sequences of bacterial 16S ribosomal RNAs (16S rRNA analysis), or whole genome shotgun metagenome analysis, and all of these comprehensively identify the types of microorganisms constituting microbiota. However, 16S rRNA analysis has a problem in that it cannot be ruled out that there may be present unknown microorganisms that cannot be amplified by PCR, or even if all of the types of microorganisms can be identified, it is difficult to analyze them quantitatively. Whole genome shotgun metagenome analysis is much more accurate than 16S rRNA analysis; however, it is laborious, time-consuming, and expensive, due to analysis of all the genomes, and it is therefore not practical on a routine basis. A method for analyzing microbiota based on cross-reactive sensing is an example of a method that may solve the abovementioned problems”. The object of the invention is therefore to provide a method for analyzing microbiota that overcomes the barriers of labor, time, and expense of the current methods of analyzing indigenous microbiota.
The breadth of the claims: The claims recite (in relevant part) a method for monitoring changes in health status of an animal over time comprising dissolving a probe capable of non-specifically interacting with two or more microorganisms in a plurality of solvents, adding a test sample containing a microbiota derived from the animal to the probe solution, measuring fluorescence intensity of the probe solution, and analyzing the pattern of fluorescence, wherein the probe comprises a cationic polymer comprising at least five primary amino groups in one molecule having a weight-average MW of 1,000 – 500,000 and an environment-sensitive fluorophore covalently bound to 1-50% of the primary amino groups in the cationic polymer. Aside from the recited molecular weight range, a cationic polymer with at least five amine groups and a fluorophore, the claimed probe is otherwise structurally unlimited. The term “microorganism” is a broad term in the art which encompasses bacteria, fungi, archaea and protozoa, and as the instant specification at [para 0038] states the "microorganisms" that the probe targets may be any microorganism in any class, such as a bacterium, fungus, protozoan, or virus, and may be a mixture of microorganisms in a plurality of classes thereof, the claimed method encompasses the non-specific interaction of all probes comprising a cationic polymer with at least five amine groups and a fluorophore at the specified MW range with all microorganisms in a microbiota.
The state of the prior art; The level of one of ordinary skill; and The level of predictability in the art: According to MPEP 2164.03, “…what is known in the art provides evidence as to the question of predictability” and “[I]f one skilled in the art cannot readily anticipate the effect of a change within the subject matter to which that claimed invention pertains, then there is lack of predictability in the art.”
As noted above, other than recited molecular weight range, a cationic polymer with the occurrence of at least five amine groups and a fluorophore, the claimed probe is otherwise structurally unlimited. Additionally, the "microorganism" as claimed to non-specifically interact with the probe in the method encompasses all microorganisms of bacteria, fungi, protozoa, archaea and virus.
National Institute of Advanced Industrial Science and Technology et al. (WO 2018/088510 A1; cited on the IDS submitted 12/02/2021; reference is made to a machine translation cited on the Form PTO-892 mailed 08/05/2024; herein NIAIST) discloses cross-reactive sensing method for analyzing a protein-containing sample comprising dissolving a probe capable of non-specifically interacting with a plurality of proteins, wherein the probe comprises a cationic polymer comprising at least five primary amino groups in one molecule and having a weight average molecular weight of 1,000 to 500,000 and an environment-sensitive fluorophore covalently bonded to a part of the primary amino group in the cationic polymer [claim 1], wherein the fluorophore is bound to preferably 1-50% of the primary amino groups of the cationic polymer [p 4, para 13]. The method of NIAIST involves non-specifically interacting the probe in the analysis sample with protein [claim 1]. As the method of NIAIST relates to the non-specific interaction of probes with proteins associated with microorganisms, but without protein extraction steps, the proteins detected by the method of NIAIST are considered to include proteins present on the surface of the microorganisms, and therefore the method is interpreted to encompass the non-specific interaction of probes with microorganisms.
However, Applicant’s Declaration under 37 CFR 1.132 states in response to the disclosure of NIAIST at [para 7] that protein cross-reactive probes cannot access proteins in Gram-negative bacteria due to their outer membrane architecture, and that even if such probes could access surface proteins, their amount and variety would be too limited, and therefore one of skill in the art would not attempt to apply protein cross-reactive probes to microbiota.
While the probe of NIAIST is encompassed by the structural limitations of the probe set forth in the claims, Applicant’s Declaration asserts the probe of NIAIST would not function in the claimed method, as surface protein information is insufficient for such characterizations given the inaccessibility of proteins on the cell surface of Gram-negative bacteria, and therefore one of skill in the art would understand that protein-cross reactive probes cannot access proteins of these microorganisms. In accordance with the statements of Applicant’s Declaration, one of skill in the art would have recognized a high level of unpredictability that all probes comprising a cationic polymer with at least five primary amino groups in one molecule having a weight-average MW of 1,000 – 500,000 and an environment-sensitive fluorophore covalently bound to 1-50% of the primary amino groups in the cationic polymer are capable of non-specifically interacting with all microorganisms in a microbiota as encompassed by the claims to maintain the desired activity/utility.
The amount of direction provided by the inventor and The existence of working examples: The specification discloses the following working examples of the recited probe and microbiota samples comprising microorganisms:
The use of probes 1-12 according to Example 2 [specification para 0076] for the discrimination among bacterial isolates listed in Table 1 [specification para 0077], and the use of probes 1, 3, 6-8 and 11 for the discrimination of microbiota samples according to Examples 5-7 [specification beginning at para 0087].
Other than these working examples, the specification fails to disclose any other probe non-specifically interacting with a microorganism from a microbiota sample. Also, the specification fails to provide guidance for using those probes that are non-functional in terms of non-specific interaction with all microorganisms, or have activity other than the expected non-specific interaction with all microorganisms.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure: While methods of interacting fluorescent probes with microorganisms were known at the time of the invention, it was not routine in the art to make and determine a use for all probes comprising a cationic polymer with at least five primary amino groups in one molecule having a weight-average MW of 1,000 – 500,000 and an environment-sensitive fluorophore covalently bound to 1-50% of the primary amino groups in the cationic polymer and interacting them with all microorganisms as recited by the claims.
In view of the overly broad scope of the claims, the lack of guidance and working examples provided in the specification, the high level of unpredictability, and the state of the prior art, undue experimentation would be necessary for a skilled artisan to make and use the entire scope of the claimed invention. Applicants have not provided sufficient guidance to enable one of ordinary skill in the art to make and use the claimed invention in a manner reasonably correlated with the scope of the claims. The scope of the claims must bear a reasonable correlation with the scope of enablement (In re Fisher, 166 USPQ 19 24 (CCPA 1970)). Without sufficient guidance, determination of having the desired biological characteristics is unpredictable and the experimentation left to those skilled in the art is unnecessarily, and improperly, extensive and undue. See In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988).
Response to Remarks: beginning on page 4 of Applicant’s response to rejections under 35 USC 112(a); Applicant in summary contends there is no genus of probes that needs to be defined beyond what is described in the specification due to the “zoomed out” fingerprinting approach of the invention, wherein the method generates a fingerprint pattern from the aggregate response of multiple probes to the entire microbiota, and does not require predicting individual probe-microorganism interactions; Applicant further contends there is no requirement for any particular species of microorganism to be bound to the probe, and therefore there is no genus of microorganisms that need to be defined beyond what is described in the specification, wherein Example 4 from the previous office action should be considered in addition to key working examples of Examples 6-7 as these are drawn to microbiota samples rather than individual bacterial species; Applicant further contends the probes do interact with microbiota including Gram-negative bacteria, as the Declaration submitted under 37 CFR 1.132 on 08/04/2025 merely states that the probes cannot access proteins in Gram-negative bacteria and not that probes cannot react with Gram-negative bacteria at all, as the claimed method is drawn to non-specific interaction with microorganisms that include cell surface molecules such as LPS, for example.
Applicant’s remarks are considered and found not convincing.
Regarding the assertion that there is no genus of probes that needs to be defined beyond what is described in the specification due to the “zoomed out” fingerprinting approach of the invention, wherein the method generates a fingerprint pattern from the aggregate response of multiple probes to the entire microbiota, and does not require predicting individual probe-microorganism interactions:
The claims do not recite a fingerprinting approach or the generation of a fingerprint pattern. The claims recite (in relevant part) a method of non-specifically adding a genus of probes, wherein the probes contain at least five primary amino groups in one molecule having a weight-average MW of 1,000 – 500,000 and an environment-sensitive fluorophore covalently bound to 1-50% of the primary amino groups in the cationic polymer, to a sample containing microbiota, wherein the probes non-specifically interact with a microorganism in the microbiota. Therefore, as stated above, the claims recite a genus of probes that are widely variant with respect to structure, and interacting said probes with a genus of microorganisms that are widely variant with respect to structure.
Regarding the assertion that there is no requirement for any particular species of microorganism to be bound to the probe, and therefore there is no genus of microorganisms that need to be defined beyond what is described in the specification:
The claims recite that the genus of probes interacts with a microorganism from the genus of microorganisms. These genera are widely variant with respect to structure, and the specification provides examples of 12 probes for individual identification of bacterial species from the genus of microorganisms, wherein the group bacteria can itself be considered a genus widely variant with respect to structure, and 6 examples of probes that interact with microbiota samples with undefined members of the genus of microorganisms. As the claims require the interaction of a probe with a microorganism from a microbiota sample, and the specification provides examples of 6 probes among a widely variant genus that interact with microbiota samples, and no examples of probes shown to interact with any microorganism among a widely variant genus in a microbiota sample, one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus of probes and the genus of microorganisms.
Regarding the assertion that Example 4 from the previous office action should be considered in addition to key working examples of Examples 6-7 as these are drawn to microbiota samples rather than individual bacterial species: the example used in the rejection of the previous Office action (Example 5) corresponds to experiments wherein probes are added to samples comprising microbiota to obtain a fingerprint of said sample. As Examples 6-7 additionally correspond to experiments interacting the same probes with different microbiota-containing samples, they have been included in consideration of the rejection above. These examples do not offer additional description of the genus of probes or the genus of microorganisms recited in the claims, for these examples use the same probes as Example 5, and similarly no microorganisms are identified as interacting with the probes.
Regarding the assertion that the probes do interact with microbiota including Gram-negative bacteria, and that the Declaration submitted under 37 CFR 1.132 on 08/04/2025 merely states that the probes cannot access proteins in Gram-negative bacteria, but not that probes cannot react with Gram-negative bacteria at all, as the claimed method is drawn to non-specific interaction with microorganisms that include cell surface molecules such as LPS, for example:
As stated in the rejection above, the statements disclosed in the Declaration submitted under 37 CFR 1.132 on 08/04/2025 support the structural variance of the genus of probes and genus of microorganisms recited in the claim, as the Declaration discloses the probe of NIAIST, which is encompassed by the structural limitations of the probe set forth in the claims, would not function in the claimed method, as surface protein information is insufficient for such characterizations given the inaccessibility of proteins on the cell surface of Gram-negative bacteria, and therefore one of skill in the art would understand that protein-cross reactive probes cannot access proteins of these microorganisms. Therefore, one of skill in the art would have recognized a high level of unpredictability that all probes comprising a cationic polymer with at least five primary amino groups in one molecule having a weight-average MW of 1,000 – 500,000 and an environment-sensitive fluorophore covalently bound to 1-50% of the primary amino groups in the cationic polymer are capable of non-specifically interacting with all microorganisms in a microbiota as encompassed by the claims to maintain the desired activity/utility.
Claim Rejections - 35 USC § 101
Claims 1-5, 7-9 and 11-12 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more. The claims below were evaluated using “Subject Matter Eligibility Test for Products and Processes” as shown in MPEP 2016 III.
The instant rejection is maintained from the previous Office Action and any newly recited portions are necessitated by claim amendment.
Patent Eligibility Analysis Step 1: The claim is drawn to a process (method) which is one of the four statutory categories.
Patent Eligibility Analysis Step 2A Prong 1: The claims are directed towards the abstract ideas of “analyzing … by multivariate analysis”, “statistically identifying”, “comparing” and “monitoring” recited in step (4) of independent claim 1. In the broadest reasonable interpretation of the claim, “analyzing … by multivariate analysis” corresponds to the mental activity of evaluating data produced by a multivariate analysis, which itself is drawn to the mental activity of manually calculating multivariate statistics on a dataset; “statistically identifying” corresponds to the mental activity of interpreting data to arrive at a conclusion based on a pre-determined numerical threshold; “comparing” corresponds to the mental activity of analyzing at least two data values to reach a conclusion; and “monitoring” corresponds to the mental activity of observing data as it is produced. Accordingly, claims 1-5, 7-9 and 11-12 are directed to a judicial exception.
Patent Eligibility Analysis Step 2A Prong 2: Claim 1 includes the additional elements of “dissolving a probe” in step (1), “adding a test sample… without protein extraction” and “wherein the probe non-specifically interacts with a microorganism” in step (2), and “measuring fluorescence intensities” in step (3). However, the additional elements in steps (1)-(3) are directed to data gathering needed to carry out the abstract idea. Data gathering does not impose any meaningful limitation on the abstract idea, or how the abstract idea is performed. Data gathering steps are not sufficient to integrate an abstract idea into a practical application as they are considered insignificant extra-solution activity (MPEP 2106.05(g)). There are no additional elements recited in claims 2-5, 7-9 and 11-12 beyond the judicial exception.
Patent Eligibility Analysis Step 2B: Goncalves et al. (Chem Rev, 2009, 109:190; cited on the attached Form PTO-892; herein referred to as Goncalves) reviews the fluorescent labeling of biomolecules with organic probes [title] and discloses that organic fluorophores may form covalent or noncovalent linkages with samples to be analyzed, and that the resulting conjugates or complexes can vary in fluorescence wavelength depending on the probe used [p 190, col 2, para 5], and discusses the optical properties of bis-squaraine dyes as an example in various solutions, wherein the measured fluorescent properties change based on the solution in which the probe is dissolved [Table 9]. Furthermore, National Institute of Advanced Industrial Science and Technology et al. (WO 2018/088510 A1; cited on the IDS submitted 12/02/2021; reference is made to a machine translation cited on the Form PTO-892 mailed 08/05/2024; herein referred to as NIAIST) discusses a method in [claim 1] for analyzing a protein-containing sample [title] comprising (1) dissolving a probe capable of non-specifically interacting with a plurality of proteins in a plurality of solvents having different ionic strengths and pH levels, (2) adding an analysis sample containing one or more proteins to a plurality of probe solutions prepared in step (1), and non-specifically interacting the probe in the analysis sample with protein, (3) measuring fluorescence intensities of the plurality of probe solutions to which the test sample has been added in step (2), and (4) comparing the fluorescence intensities obtained in step (3) with the fluorescence intensities obtained from a reference sample. As the method of NIAIST does not disclose the use of protein extraction, it is considered that the method is carried out without protein extraction. NIAIST further teaches the protein targeted by the probe may be any protein having an arbitrary amino acid sequence, and may be any protein derived from animals, plants, microorganisms or viruses [p 4, para 2], and the examples of analysis sample include biological fluids samples such as blood, serum, plasma, urine and saliva, which is considered to correspond to a sample derived from an animal that comprises microorganisms. As the method of NIAIST relates to the non-specific interaction of probes with proteins associated with microorganisms without protein extraction steps, the proteins are interpreted as present on the surface of the microorganisms, and therefore the method is interpreted to encompass the non-specific interaction of probes with microorganisms.
In view of Goncalves and NIAIST, the additional elements of “dissolving a probe” in step (1), “adding a test sample… without protein extraction” and “wherein the probe non-specifically interacts with a microorganism” in step (2), and “measuring fluorescence intensities” in step (3) are considered to be well-understood, routine and conventional activities previously known to the industry (MPEP 2106.05(d)), and therefore the judicial exception is recited without additional limitations amounting to significantly more than the exception. All of the signified additional elements to the judicial exception are considered to be required data collection steps of the judicial exception that are well-understood, routine and conventional, and, therefore, do not amount to significantly more than the judicial exception that is claimed.
As the instant claims recite judicial exceptions that are not integrated into a practical application, and no elements that amount to significantly more than the judicial exception as recited, the claims were found not to be drawn to eligible subject matter under 35 U.S.C. 101.
Response to Remarks: beginning on page 6 of Applicant’s response to rejections under 35 USC 101; Applicant in summary contends the claims do not recite an abstract idea because while the claims involve analyzing, comparing and monitoring steps, the inventive method of monitoring the health status of an animal using a probe comprising a cationic polymer and an environment-sensitive fluorophore does not recite a judicial exception (JE); Applicant further contends the recited additional elements integrate the JE at Step 2A2 as they constitute an improvement in a technical field in view of the lack of protein extraction step and the generated multi-dimensional fluorescence patterns to discriminate complex microbiota with a high degree of accuracy; Applicant further contends the recited additional elements integrate the JE into the practical application of identifying changes in health conditions and monitoring changes in health status;
Applicant further contends the additional elements amount to significantly more than the JE itself in Step 2B as they constitute an improvement to existing technology, as the claimed method is applied with a particular probe with a specific structure.
Applicant’s remarks are considered and found not convincing.
Regarding the assertion that the claims do not recite an abstract idea because while the claims involve analyzing, comparing and monitoring steps, the inventive method of monitoring the health status of an animal using a probe comprising a cationic polymer and an environment-sensitive fluorophore does not recite a judicial exception (JE):
As stated in the rejection above at Step 2A1, the claims are directed towards the abstract ideas of “analyzing … by multivariate analysis”, “statistically identifying”, “comparing” and “monitoring” recited in step (4) of independent claim 1. In the broadest reasonable interpretation of the claim, “analyzing … by multivariate analysis” corresponds to the mental activity of evaluating data produced by a multivariate analysis, which itself is drawn to the mental activity of manually calculating multivariate statistics on a dataset; “statistically identifying” corresponds to the mental activity of interpreting data to arrive at a conclusion based on a pre-determined numerical threshold; “comparing” corresponds to the mental activity of analyzing at least two data values to reach a conclusion; and “monitoring” corresponds to the mental activity of observing data as it is produced. Accordingly, claims 1-5, 7-9 and 11-12 are directed to a judicial exception.
Regarding the assertion that the recited additional elements integrate the JE at Step 2A2 as they constitute an improvement in a technical field in view of the lack of protein extraction step and the generated multi-dimensional fluorescence patterns to discriminate complex microbiota with a high degree of accuracy:
Step 2A2 involves the identification of additional elements, and as stated above the additional elements of “dissolving a probe” in step (1), “adding a test sample… without protein extraction” and “wherein the probe non-specifically interacts with a microorganism” in step (2), and “measuring fluorescence intensities” in step (3) are directed to data gathering needed to carry out the abstract idea. Data gathering does not impose any meaningful limitation on the abstract idea, or how the abstract idea is performed. Data gathering steps are not sufficient to integrate an abstract idea into a practical application as they are considered insignificant extra-solution activity (MPEP 2106.05(g)). Additionally, it is noted the claims do not recite limitations of generating multi-dimensional fluorescence patterns to discriminate complex microbiota with a high degree of accuracy.
Regarding the assertion that the recited additional elements integrate the JE into the practical application of identifying changes in health conditions and monitoring changes in health status: the practical applications cited by Applicant are themselves JEs identified in Step 2A1 of the rejection above.
Regarding the assertion that the additional elements amount to significantly more than the JE itself in Step 2B as they constitute an improvement to existing technology, as the claimed method is applied with a particular probe with a specific structure: the claims do not recite a particular probe with a specific structure. As this limitation is not present in the claims, it is therefore not cited as an additional element, and ultimately not considered at Step 2B in the determination of whether the recited additional elements amount to significantly more than the JE.
Claim Rejections - 35 USC § 103
Claims 1, 4-5, 7-9 and 11-12 are rejected under 35 U.S.C. 103 as being unpatentable over National Institute of Advanced Industrial Science and Technology et al. (WO 2018/088510 A1; cited on the IDS submitted 12/02/2021; reference is made to a machine translation cited on the Form PTO-892 mailed 08/05/2024; herein NIAIST) in view of Lai et al. (Methods in Biol, 2018, 1871:123-132; cited on the IDS submitted 12/02/2021; herein Lai) and Samanta et al. (J Microbiol, 2012, 50:218; cited on the attached Form PTO-892; herein Samanta).
The instant rejection is maintained from a previous office action. Any newly recited portions are necessitated by claim amendment.
Claim 1 is drawn to a method for monitoring changes in health status of an individual animal over time, comprising:
(1) dissolving a probe capable of non-specifically interacting with two or more microorganisms in a plurality of solvents having different ionic strengths and pH levels, wherein the probe comprises:
(a) a cationic polymer comprising at least five primary amino groups in one molecule and having a weight-average molecular weight of 1,000 to 500,000 and
(b) an environment-sensitive fluorophore, wherein the fluorophore is covalently bonded to 1% to 50% of the primary amino groups in the cationic polymer;
(2) repeatedly adding a test sample containing a microbiota derived from the individual animal over time to a plurality of probe solutions prepared in the step (1), without protein extraction,
wherein the microbiota comprises a plurality of microorganisms and wherein the probe non-specifically interacts with a microorganism present in the microbiota;
(3) measuring fluorescence intensities of the plurality of probe solutions to which the test sample has been added in the step (2); and
(4) analyzing the pattern of fluorescence intensities obtained in the step (3) by multivariate analysis and statistically identifying changes in the health status of the individual animal by comparing with the pattern of fluorescence intensities obtained from a reference sample, thereby monitoring changes in health status of the individual over time, wherein the health status comprises obesity, sleep disorder, or insufficient exercise.
NIAIST discusses a method for analyzing a protein-containing sample [title].
Regarding claim 1 and the limitations of step (1), NIAIST teaches a method for analyzing a protein-containing sample comprising dissolving a probe capable of non-specifically interacting with a plurality of proteins in a plurality of solvents having different ionic strengths and pH levels, wherein the probe comprises (a) a cationic polymer comprising at least five primary amino groups in one molecule and having a weight average molecular weight of 1,000 to 500,000 and (b) an environment-sensitive fluorophore covalently bonded to a part of the primary amino group in the cationic polymer [claim 1], wherein the fluorophore is bound to preferably 1-50% of the primary amino groups of the cationic polymer [p 4, para 13].
Regarding the limitations of claim 1 step (2), NIAIST teaches adding an analysis sample containing one or more proteins to a plurality of probe solutions prepared in step (1), and non-specifically interacting the probe in the analysis sample with protein [claim 1]. As the method of NIAIST does not disclose the use of protein extraction, the teachings of NIAIST are considered to encompass carrying out the method without protein extraction. NIAIST further teaches the protein targeted by the probe may be any protein having an arbitrary amino acid sequence, and may be any protein derived from animals, plants, microorganisms or viruses [p 4, para 2], and the examples of analysis sample include biological fluids samples such as blood, serum, plasma, urine and saliva [p 5, para 7], which is considered to correspond to a sample derived from an animal that comprises microorganisms. As the method of NIAIST relates to the non-specific interaction of probes with proteins associated with microorganisms without protein extraction steps, the proteins are interpreted as present on the surface of the microorganisms, and therefore the method is interpreted to encompass the non-specific interaction of probes with microorganisms.
Regarding the limitations of claim 1 step (3), NIAIST teaches measuring fluorescence intensities of the plurality of probe solutions to which the test sample has been added in step (2) [claim 1]. NIAIST additionally teaches changes in fluorescence intensity are observed when the culture supernatant of cells after different culture times is added to five type of probe solutions [p 3, para 13, middle], which is considered to correspond to the repeated addition of a sample to a probe solution.
Regarding the limitations of claim 1 step (4), NIAIST teaches comparing the fluorescence intensities obtained in step (3) with the fluorescence intensities obtained from a reference sample [claim 1], wherein the type and/or state and/or concentration of cells in culture are determined by the comparison [claim 9], and wherein the fluorescence intensity pattern reflects the sum of the non-specific interactions between various proteins and probes present in the sample [p 6, para 2]. NIAIST additionally teaches the analysis of fluorescence data by linear discriminant analysis [p 3, para 13], which is understood to be a multivariate analysis technique.
NIAIST does not teach the interaction of a probe with microorganisms from a microbiota, and statistically identifying changes in health status comprising obesity, sleep disorder, or insufficient exercise.
Lai discusses metaproteomics and the gut microbiome [title], and discloses the use of proteomics techniques for identification and quantification of protein as well as post-translational modifications provides an ideal platform to investigate the gut microbiome [abstract].
Regarding claim 1 and the limitation of monitoring changes in the health status of an animal over time by observing changes in the microbiota, Lai teaches that metaproteomics is the comprehensive characterization of expressed proteins within a microbiome community at a given point in time [p 125, para 4], wherein exemplary targeted proteomics methods have been used to evaluate the differences in Bacteroides and Clostridiales species of bacteria in samples from patients with Crohn’s disease [p 126, para 1], which corresponds to the evaluation of proteins associated with microbiota that is derived from an animal (e.g., a human with Crohn’s disease). Additionally, Lai teaches that gut microbiome analysis is utilized for biomarker development to discriminate normal individuals and diseased patients as well as to monitor disease activity and prognosis [abstract], and that analysis of the human gut microbiome has been focused in various patient cohorts where dysbiosis or an imbalance of the gut microbiota has been implicated in the pathogenesis of IDB, obesity, metabolic disorders, and cardiovascular disease [p 124, para 3], which corresponds to the evaluation of patient microbiota to monitor changes in health status associated with the pathogenesis of obesity. As the method of Lai is carried out to evaluate proteins associated with complex microbiota, and therefore evaluate changes in microbiota composition, in order to monitor health status of a patient, and draw conclusions about both the microbiota and the patient from which the microbiota originated, one of skill in the art would reasonably conclude that the method of NIAST could be applied to microbiota to similarly evaluate multiple bacterial species and draw conclusions about the patient whose sample is being evaluated as suggested by Lai.
Samanta relates to the detection of unique bacterial communities in faecal microbiota of rats with experimentally-induced colitis [title], and discusses methods of studying the gut microbiota that overcome the known impediment in the field of growing the gut inhabiting microbes in order to understand the microbial community changes associated with diseases that are poorly understood [p 218, col 2, para 1].
Regarding claim 1 and the limitation of analyzing by multivariate analysis and statistically identifying changes in health status, Samanta teaches that in some intestinal diseases such as Crohn’s, there is a decreased microbial diversity in intestinal tissues along with increases and decreases in certain bacterial phyla [p 218, col 2, para 2], and discloses a method of monitoring rat microbiome diversity by analyzing operational taxonomic units (OTU) of bacteria with multivariate analysis to compare diseased and control faecal samples [p 220, col 1, para 2] and analyzing similarity percentages to determine which observed OTU contributed greatest to the dissimilarity between healthy and diseased rats [p 220, col 1, para 3], which corresponds to multivariate analysis of collected data and the statistic identification of changes in the microbiota associated with a change in health status. As Samanta teaches this method of analyzing data obtained from microbiome studies to understand the community changes associated with diseases that are poorly understood and have traditionally been impeded by problematic laboratory experimental practices, one of skill in the art would be motivated modify the method of NIAIST by applying multivariate analysis of data to statistically identify changes in the microbiota associated with a change in health status, as taught by Samanta.
In view of NIAIST, Lai and Samanta, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of NIAIST by analyzing samples comprising microbiota as taught by both Lai and Samanta, to monitor changes in health status associated with obesity as taught by Lai, and by analyzing microbiome community data by multivariate analysis to statistically identify changes in health status as taught by Samanta, to arrive at the claimed invention.
One of ordinary skill in the art would have been motivated to modify the method of NIAIST by analyzing microbiota, because Lai teaches methods of gut microbiome analysis comprising evaluation of microbiota that are utilized for biomarker development to discriminate normal individuals and diseased patients as well as to monitor disease activity and prognosis.
One of ordinary skill in the art would have been motivated to modify the method of NIAIST by using the method to monitor changes in health status associated with obesity, because Lai teaches analysis of the human gut microbiome can be focused in various patient cohorts where dysbiosis or an imbalance of the gut microbiota has been implicated in the pathogenesis of IDB, obesity, metabolic disorders, and cardiovascular disease.
One of ordinary skill in the art would have been motivated to modify the method of NIAIST by analyzing the fluorescence data generated by the method of NIAIST by multivariate analysis to statistically identify changes in health status because Samanta teaches statistically analyzing data obtained from microbiome studies to understand the community changes associated with diseases that are poorly understood and have traditionally been impeded by problematic laboratory experimental practices.
One of ordinary skill in the art would have had a reasonable expectation of success because NIAIST and Lai relate to methods for identifying proteins in microbial samples, and Lai and Samanta relate to methods for microbiome analysis associated with monitoring health status changes.
Regarding claim 4, NIAIST teaches the cationic polymer is a linear or branched polyamino acid, polyallylamine, polyamidoamine, or polyalkyleneimine [claim 3].
Regarding claim 5, NIAIST teaches the polyamino acid is polylysine or polyornithine [claim 4].
Regarding claim 7, NIAIST teaches the introduction of a functional group to environment-responsive fluorophore of the cationic polymer selected from the group consisting of a guanidium group, an alkyl group, an aryl group, carboxyl group, and an amino acid with respect to at least part of the primary amino group that is not covalently bonded [claim 6], and that the fluorophore is bound to preferably 1-50% of the primary amino group of the cationic polymer [p 4, para 13].
Regarding claim 8, NIAIST teaches the measurement of the fluorescence intensities is performed at a plurality of excitation wavelengths and emission wavelengths [claim 7].
Regarding claim 9, NIAIST teaches the method described in the rejection of claim 1 wherein the types and/or amounts of protein in the sample are determined by step (4) [claim 8], and Lia teaches the use of protein identification and quantitation techniques to investigate the gut microbiome [abstract].
Regarding claims 11-12, Lai teaches the characteristics of human patients with Crohn’s disease based on the analysis of proteins from patient-derived samples that can be traced to particular bacterial species [p 126, para 1], wherein the patient-derived samples are understood to encompass gut microbiota.
Therefore, the invention of claims 1, 4-5, 7-9 and 11-12 would have been obvious to one of ordinary skill in the art before the effective filing date.
Claims 2-3 are rejected under 35 U.S.C. 103 as being unpatentable over NIAIST in view of Lai and Samanta as applied to claims 1, 4-5, 7-9 and 11-12 above, and further in view of Wang et al. (Org Biomol Chem, 2011, 9:2219; cited on the Form PTO-892 mailed 08/05/2024; herein referred to as Wang).
The instant rejection is maintained from a previous office action. Any newly recited portions are necessitated by claim amendment.
Claim 2 is drawn to the method of claim 1, wherein the environment-sensitive fluorophore is an aggregation-induced emission fluorophore.
The teachings of NIAIST, Lai and Samanta as applied to claims 1, 4-5, 7-9 and 11-12 are discussed above. These references do not teach an aggregation-induced fluorophore.
Wang discusses the novel fluorescent probe tetraphenylethylene [title] and discloses its use for studies of carbohydrate-protein interaction.
Regarding claim 2, Wang teaches neutral sugar-bearing tetraphenylethylenes are “turn-on” luminescent sensors based on aggregation-induced emission [abstract] and discusses the use of tetraphenylethylene derivatives as a scaffold for potential sensing purposes wherein the aggregation-induced emission effect of these molecules can greatly improve the fluorescence quantum yields by up to 3 orders of magnitude [p 2219, col 1, para 2 to col 2, para 2].
In view of Wang, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined method of NIAIST, Lai and Samanta by using the fluorophore of Wang to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to modify the combined method of NIAIST, Lai and Samanta by using an aggregation-induced fluorophore because Wang teaches that aggregation-induced emission fluorophores can improve fluorescence quantum yield up to 3 orders of magnitude and can be used to detect biomolecule interactions. One of ordinary skill in the art would have had a reasonable expectation of success because NIAIST, Lai and Wang discuss methods for protein detection.
Regarding claim 3, Wang teaches the aggregation-induced emission fluorophore tetraphenylethylene [p 2219, col 1, para 2 to col 2, para 2] discussed above.
Therefore, the invention of claims 2-3 would have been obvious to one of ordinary skill in the art before the effective filing date.
Response to Remarks: beginning page 8 of Applicant’s response to rejections under 35 USC 103; Applicant in summary contends (1) a person of ordinary skill in the art would not reasonably expect the probe of NIAIST to carry out all the functions of the claimed probe, as the probe recited in the claims interacts with the entire microbial surface including LPS, peptidoglycans, teichoic acids, polysaccharides and membrane lipids while the probe of NIAIST interacts with protein; Applicant further contends (2) the NIAIST method would not be considered a microorganism detection method by one of ordinary skill in the art, and would not be able to provide a fingerprint of all the microorganisms present in a sample, as there is a significant leap from knowing a probe can bind proteins to expecting the probe can bind the majority of microorganisms in a sample, which is not supported by the disclosure of NIAIST; Applicant further contends (3) the claimed method is performed without protein extraction, and the absence of protein extraction in the NIAIST method is merely incidental and not a teaching of a method lacking protein extraction, wherein one of ordinary skill in the art would not reasonably expect such a method to work well for analyzing cell surfaces of intact microbiota; Applicant further contends (4) any obviousness rejection would be overcome by secondary indicia of non-obviousness including solving a long-felt need, failure of others, and unexpected results, citing the long-felt need to discriminate complex microbiota to diagnose various conditions which others have failed to solve; Applicant further contends (5) the present invention contains the unexpected high degree of accuracy of 91-94% (Example 6) and 100% (Example 7) to discriminate the microbiota of sleep disorder mice and mice with insufficient exercise, respectively, and that it is unexpected for the probe of NIAIST to not only bind proteins but other surface molecules as to accurately determine microbiota patterns; Applicant further contends (6) the aggregation-induced fluorophore of Wang does not teach the claimed fluorophore as Wang does not teach such fluorophores and tetraphenylethylenes covalently bonded to primary amino groups of cationic polymer that are designed to detect non-specific interactions with a variety of cell surface molecules; Applicant further contends (7) there is no motivation to combine the NIAIST probe with the Wang probe, and one of ordinary skill in the art would not reasonably expect the combination to function in detecting non-specific interactions across the entire microbial surface in complex microbiota and discriminate microbial populations of animals with different health statuses.
Regarding the assertion that a person of ordinary skill in the art would not reasonably expect the probe of NIAIST to carry out all the functions of the claimed probe, as the probe in the claims interacts with the entire microbial surface including LPS, peptidoglycans, teichoic acids, polysaccharides and membrane lipids while the probe of NIAIST interacts with protein:
The claims do not recite a probe that interacts with the entire microbial surface including LPS, peptidoglycans, teichoic acids, polysaccharides and membrane lipids. Rather, the claims recite that the probe non-specifically interacts with a microorganism present in the microbiota.
Regarding the assertion that the NIAIST method would not be considered a microorganism detection method by one of ordinary skill in the art, and would not be able to provide a fingerprint of all the microorganisms present in a sample, as there is a significant leap from knowing a probe can bind proteins to expecting the probe can bind the majority of microorganisms in a sample, which is not supported by the disclosure of NIAIST:
The claims do not recite providing a fingerprint of all the microorganisms present in a sample, and do not recite the binding of the majority of microorganisms in a sample. The claims instead recite that the probe non-specifically interacts with a microorganism present in the microbiota.
Regarding the assertion that the claimed method is performed without protein extraction, and the absence of protein extraction in the NIAIST method is merely incidental and not a teaching of a method lacking protein extraction, wherein one of ordinary skill in the art would not reasonably expect such a method to work well for analyzing cell surfaces of intact microbiota:
The claims do note recite a method for analyzing cell surfaces of intact microbiota. The claims instead recite a method for monitoring changes in health status of an individual animal over time comprising a probe that non-specifically interacts with a microorganism present in the microbiota.
Regarding the assertion that any obviousness rejection would be overcome by secondary indicia of non-obviousness including solving a long-felt need, failure of others, and unexpected results, citing the long-felt need to discriminate complex microbiota to diagnose various conditions which others have failed to solve:
The claims do not recite a method comprising the discrimination of complex microbiota to diagnose various conditions.
Regarding Applicant’s allegations of unexpected results, Applicant alleges the present invention contains the unexpected high degree of accuracy of 91-94% (Example 6) and 100% (Example 7) to discriminate the microbiota of sleep disorder mice and mice with insufficient exercise, respectively, and that it is unexpected for the probe of NIAIST to not only bind proteins but other surface molecules as to accurately determine microbiota patterns:
MPEP 716.02(e) states the subject matter must be compared with the closest prior art to be effective to rebut a prima facie case of obviousness. As Applicant has not compared the proffered results to any prior art, Applicant has not satisfied the requirements of MPEP 716.02(e).
MPEP 716.02(b) states the burden is on Applicant to establish results are unexpected and significant, and that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance. The examples proffered by Applicant associated with the cited high accuracy are the result of comparisons within the same experiment, as Applicant has not compared these data to the prior art as stated above, it is unclear why these results are unexpected and significant against the prior art, and why these results are of practical significance. Therefore, Applicant has not satisfied the requirements of MPEP 716.02(b).
MPEP 716.02(d) states unexpected results must be commensurate in scope with the claimed invention. As the data in the Examples proffered by Applicant correspond to experiments using 6 probes with two types of microbiota-containing samples (and relevant controls), the results are not commensurate in scope with the claimed method that encompasses: (a) all probes comprising a cationic polymer comprising at least five primary amino groups in one molecule and having a weight-average molecular weight of 1,000 to 500,000; (b) the interaction of said probes with all microorganisms in all microbiota-containing samples; (c) identifying changes in health status of all animals; and (d) identifying changes in the health statuses of said animals of obesity, sleep disorder, and insufficient exercise. Therefore, Applicant has not satisfied the requirements of MPEP 716.02(d).
For these reasons, Applicant’s allegations of unexpected results are considered and found insufficient to rebut a prima facie case of obviousness.
Regarding the assertion that the aggregation-induced fluorophore of Wang does not teach the claimed fluorophore as Wang does not teach such fluorophores and tetraphenylethylenes covalently bonded to primary amino groups of cationic polymer that are designed to detect non-specific interactions with a variety of cell surface molecules, and that there is no motivation to combine the NIAIST probe with the Wang probe:
The claims do not recite the detection of non-specific interactions of a probe with a variety of cell surface molecules. The claims instead recite that the probe non-specifically interacts with a microorganism present in the microbiota. Additionally, the design intent of the claimed probe is not a claimed feature of the invention, but would be considered an intended use of the probe that does not structurally limit the probe being claimed in the method of claims 2-3. Regarding the function of the probe, as the probe of the combined method of NIAIST, Lai, Samanta and Wang is encompassed by the structural limitations of the probe in the claim as described in the rejection above, it is considered to have the function of detecting non-specific interactions with a variety of cell surface molecules, as MPEP 2112.01 states when the structure recited in the reference is substantially identical to that of the claimed, the claimed properties or functions are presumed to be inherent.
While Wang may not teach the binding of the fluorophore to the amino groups of a cationic polymer, NIAIST teaches a probe comprising (a) a cationic polymer comprising at least five primary amino groups in one molecule and having a weight average molecular weight of 1,000 to 500,000 and (b) an environment-sensitive fluorophore covalently bonded to a part of the primary amino group in the cationic polymer [claim 1]. As NIAIST teaches the architecture of the probe design and both the linkage sites and linkage types of an environmental-sensitive fluorophore to the probe, and Wang teaches an environmentally-sensitive fluorophore, it would have been obvious to modify the combined method of NIAIST, Lai and Samanta by using the fluorophore of Wang to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to modify the combined method of NIAIST, Lai and Samanta by using an aggregation-induced fluorophore because Wang teaches that aggregation-induced emission fluorophores can improve fluorescence quantum yield up to 3 orders of magnitude and can be used to detect biomolecule interactions.
Regarding the assertion that one of ordinary skill in the art would not reasonably expect the combination of NIAIST, Lai, Samanta and Wang to function in detecting non-specific interactions across the entire microbial surface in complex microbiota and discriminate microbial populations of animals with different health statuses:
The claims do not recite detecting non-specific interactions across the entire microbial surface in complex microbiota and discriminating microbial populations of animals with different health statuses.
Double Patenting
Claims 1, 4-5, 7-9 and 11-12 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 3-8 of U.S. Patent No. 11,397,185 (cited on the Form PTO-892 mailed 08/05/2024; herein “patent”) in view of NIAIST, Lai and Samanta.
The instant rejection is maintained from a previous office action. Any newly recited portion is necessitated by claim amendment.
Regarding instant claim 1, claim 1 of the patent recites a method for analyzing a protein-containing sample comprising the steps of (1) dissolving a probe capable of non-specifically interacting with a plurality of proteins in a plurality of solvents having different ionic strengths and pH levels, wherein the probe comprises (a) a cationic polymer comprising at least five primary amino groups in one molecule and having a weight average molecular weight of 1,000 to 500,000 and (b) an environment-sensitive fluorophore covalently bonded to a part of the primary amino group in the cationic polymer; (2) adding an analysis sample containing one or more proteins to a plurality of probe solutions prepared in step (1), and non-specifically interacting the probe in the analysis sample with protein; (3) measuring fluorescence intensities of the plurality of probe solutions to which the test sample has been added in step (2); and (4) comparing the fluorescence intensities obtained in step (3) with the fluorescence intensities obtained from a reference sample, and claim 5 of the patent recites the environment-sensitive fluorophore is covalently bonded to 1 to 50% of the primary amino groups in the cationic polymer. As the claims of the patent do not recite the application of protein extraction, the method of the patent is considered to be carried out without protein extraction.
The claims of the patent do not recite the interaction of a probe with microorganisms or a test sample containing microbiota and the limitations of step (4) of the instant claim.
NIAIST discusses a method for analyzing a protein-containing sample [title] for providing an easy and highly accurate analysis method capable of solving problems for elucidating pathogenesis and pathology of diseases associated with common techniques that rely on the use of polyclonal antibodies [p 1, paras 2-3 and 6].
Regarding instant claim 1 and the limitations of step (1), NIAIST discloses a method for analyzing a protein-containing sample comprising the steps of (1) dissolving a probe capable of non-specifically interacting with a plurality of proteins in a plurality of solvents having different ionic strengths and pH levels, wherein the probe comprises (a) a cationic polymer comprising at least five primary amino groups in one molecule and having a weight average molecular weight of 1,000 to 500,000 and (b) an environment-sensitive fluorophore covalently bonded to a part of the primary amino group in the cationic polymer [claim 1], wherein the fluorophore is bound to preferably 1-50% of the primary amino group of the cationic polymer [p 4, para 13].
Regarding the limitations of instant claim 1 step (2), NIAIST discloses adding an analysis sample containing one or more proteins to a plurality of probe solutions prepared in step (1), and non-specifically interacting the probe in the analysis sample with protein [claim 1]. As the method of NIAIST does not disclose the use of protein extraction, it is considered that the method is carried out without protein extraction. NIAIST further discloses the protein targeted by the probe may be any protein having an arbitrary amino acid sequence, and may be any protein derived from animals, plants, microorganisms or viruses [p 4, para 2], and the examples of analysis sample include biological fluids samples such as blood, serum, plasma, urine and saliva [p 5, para 7], which is considered to correspond to a sample derived from an animal that comprises microorganisms. As the method of NIAIST relates to the non-specific interaction of probes with proteins associated with microorganisms without protein extraction steps, the proteins are interpreted as present on the surface of the microorganisms, and therefore the method is interpreted to encompass the non-specific interaction of probes with microorganisms.
Regarding the limitations of claim 1 step (3), NIAIST discloses measuring fluorescence intensities of the plurality of probe solutions to which the test sample has been added in step (2) [claim 1]. NIAIST additionally discloses changes in fluorescence intensity are observed when the culture supernatant of cells after different culture times is added to five type of probe solutions [p 3, para 13, middle], which is considered to correspond to the repeated addition of a sample to a probe solution.
Regarding the limitations of claim 1 step (4), NIAIST discloses comparing the fluorescence intensities obtained in step (3) with the fluorescence intensities obtained from a reference sample [claim 1], wherein the type and/or state and/or concentration of cells in culture are determined by the comparison [claim 9], and wherein the fluorescence intensity pattern reflects the sum of the non-specific interactions between various proteins and probes present in the sample [p 6, para 2]. NIAIST additionally discloses the analysis of fluorescence data by linear discriminant analysis [p 3, para 13], which is understood to be a multivariate analysis technique.
Lai discusses metaproteomics and the gut microbiome [title], and discloses the use of proteomics techniques for identification and quantification of protein as well as post-translational modifications provides an ideal platform to investigate the gut microbiome [abstract].
Regarding instant claim 1 and the limitation of monitoring changes in the health status of an animal over time by observing changes in the microbiota, Lai discloses that metaproteomics is the comprehensive characterization of expressed proteins within a microbiome community at a given point in time [p 125, para 4], wherein exemplary targeted proteomics methods have been used to evaluate the differences in Bacteroides and Clostridiales species of bacteria in samples from patients with Crohn’s disease [p 126, para 1], which corresponds to the proteomic evaluation of proteins associated with microbiota that is derived from an animal (e.g., a human with Crohn’s disease). Additionally, Lai discloses that gut microbiome analysis is utilized for biomarker development to discriminate normal individuals and diseased patients as well as to monitor disease activity and prognosis [abstract], and that analysis of the human gut microbiome has been focused in various patient cohorts where dysbiosis or an imbalance of the gut microbiota has been implicated in the pathogenesis of IDB, obesity, metabolic disorders, and cardiovascular disease [p 124, para 3], which corresponds to the evaluation of patient microbiota to monitor changes in health status associated with the pathogenesis of obesity. As the method of Lai is carried out to evaluate proteins associated with complex microbiota in order to monitor health status of a patient, and draw conclusions about the microbiota and therefore the patient from which the microbiota originated, one of skill in the art would reasonably conclude that the method of the patent could be applied to microbiota to similarly evaluate multiple bacterial species and draw conclusions about the patient whose sample is being evaluated as suggested by Lai.
Samanta relates to the detection of unique bacterial communities in faecal microbiota of rats with experimentally-induced colitis [title], and discusses methods of studying the gut microbiota that overcome the known impediment in the field of growing the gut inhabiting microbes in order to understand the microbial community changes associated with diseases that are poorly understood [p 218, col 2, para 1].
Regarding instant claim 1 and the limitation of analyzing by multivariate analysis and statistically identifying changes in health status, Samanta discloses that in some intestinal diseases such as Crohn’s, there is a decreased microbial diversity in intestinal tissues along with increases and decreases in certain bacterial phyla [p 218, col 2, para 2], and discloses a method of monitoring rat microbiome diversity by analyzing operational taxonomic units (OTU) of bacteria with multivariate analysis to compare diseased and control faecal samples [p 220, col 1, para 2], and by analyzing similarity percentages to determine which observed OTU contributed greatest to the dissimilarity between healthy and diseased rats [p 220, col 1, para 3], which corresponds to multivariate analysis of collected data and the statistic identification of changes in the microbiota associated with a change in health status. As Samanta discloses this method of analyzing data obtained from microbiome studies to understand the community changes associated with diseases that are poorly understood and have traditionally been impeded by problematic laboratory experimental practices, one of skill in the art would be motivated to apply multivariate analysis of data to statistically identify changes in the microbiota associated with a change in health status, as disclosed by Samanta to the method of the patent.
In view of NIAIST, Lai and Samanta, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the claims of the patent by analyzing samples comprising microbiota as disclosed by both Lai and Samanta, to monitor changes in health status associated with obesity as disclosed by Lai, by comparing the pattern of sample fluorescence intensities the pattern of refence fluorescence intensities as disclosed by NIAIST, and by analyzing microbiome community data by multivariate analysis to statistically identify changes in health status as disclosed by Samanta, to arrive at the claimed invention.
One of ordinary skill in the art would have been motivated to modify the claims of the patent by analyzing microbiota, because Lai discloses methods of gut microbiome analysis comprising evaluation of microbiota that are utilized for biomarker development to discriminate normal individuals and diseased patients as well as to monitor disease activity and prognosis.
One of ordinary skill in the art would have been motivated to modify the claims of the patent by using the method to monitor changes in health status associated with obesity, because Lai discloses analysis of the human gut microbiome can be focused in various patient cohorts where dysbiosis or an imbalance of the gut microbiota has been implicated in the pathogenesis of IDB, obesity, metabolic disorders, and cardiovascular disease.
One of ordinary skill in the art would have been motivated to modify the claims of the patent by comparing fluorescence intensities to reference fluorescence intensities because NIAIST discloses an easy and highly accurate analysis method capable of solving problems for elucidating pathogenesis and pathology of diseases associated with common techniques comprising the comparison of fluorescence intensities compared to a reference.
One of ordinary skill in the art would have been motivated to modify the claims of the patent by analyzing the data generated by multivariate analysis to statistically identify changes in health status because Samanta discloses statistically analyzing data obtained from microbiome studies to understand the community changes associated with diseases that are poorly understood and have traditionally been impeded by problematic laboratory experimental practices.
One of ordinary skill in the art would have had a reasonable expectation of success because the patent, NIAIST and Lai discuss methods for identifying proteins, and Lai and Samanta discuss methods for microbiome analysis associated with monitoring health status changes.
Regarding instant claim 4, claim 3 of the patent recites the cationic polymer is a linear or branched polyamino acid, polyallylamine, polyamidoamine, or polyalkyleneimine.
Regarding instant claim 5, claim 4 of the patent recites the polyamino acid is polylysine or polyornithine.
Regarding instant claim 7, the limitation of “introduced into at least 1% to 50% of the primary amino groups” is being interpreted to as an open-ended range with the minimum varying between 1% and 50%. Claim 6 of the patent recites the introduction of a functional group to environment-responsive fluorophore of the cationic polymer selected from the group consisting of a guanidium group, an alkyl group, an aryl group, carboxyl group, and an amino acid to the primary amino group that is not covalently bonded, and NIAIST also discloses the introduction of a functional group to environment-responsive fluorophore of the cationic polymer selected from the group consisting of a guanidium group, an alkyl group, an aryl group, carboxyl group, and an amino acid with respect to at least part of the primary amino group that is not covalently bonded [claim 6], and that the fluorophore is bound to preferably 1-50% of the primary amino group of the cationic polymer [p 4, para 13]
Regarding instant claim 8, claim 7 of the patent recites the measurement of the fluorescence intensities is performed at a plurality of excitation wavelengths and emission wavelengths.
Regarding instant claim 9, claim 8 of the patent recites the method described in the rejection of claim 1 wherein the types and/or amounts of protein in the sample are determined by step (4), and Lia discloses the use of protein identification and quantitation techniques to investigate the gut microbiome [abstract].
Regarding instant claim 11-12, Lia discloses the characteristics of human patients with Crohn’s disease based on the analysis of proteins from patient-derived samples that can be traced to particular bacterial species [p 126, para 1], wherein the patient-derived samples are understood to encompass gut microbiota.
Claims 2-3 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 3-8 of U.S. Patent No. 11,397,185 in view of NIAIST, Lai and Samanta as applied to claims 1, 4-5, 7-9 and 11-12 above, and further in view of Wang.
The instant rejection is maintained from a previous office action. Any newly recited portions are necessitated by claim amendment.
The claims of the patent and disclosures of NIAIST, Lai and Samanta as applied to claims 1, 4-5, 7-9 and 11-12 are discussed above. The claims of the patent do not recite an aggregation-induced fluorophore.
Wang discusses the novel fluorescent probe tetraphenylethylene [title] and discloses its use for studies of carbohydrate-protein interaction.
Regarding instant claim 2, Wang discloses neutral sugar-bearing tetraphenylethylenes are “turn-on” luminescent sensors based on aggregation-induced emission [abstract] and discusses the use of tetraphenylethylene derivatives as a scaffold for potential sensing purposes wherein the aggregation-induced emission effect of these molecules can greatly improve the fluorescence quantum yields by up to 3 orders of magnitude [p 2219, col 1, para 2 to col 2, para 2].
In view of Wang, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined method of the patent, NIAIST, Lai and Samanta by using the fluorophore of Wang to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to modify the combined method of the patent, NIAIST and Lai because Wang discloses that aggregation-induced emission fluorophores can improve fluorescence quantum yield up to 3 orders of magnitude and can be used to detect biomolecule interactions. One of ordinary skill in the art would have had a reasonable expectation of success because the patent, NIAIST, Lai and Wang discuss methods for protein detection.
Regarding instant claim 3, Wang discloses the aggregation-induced emission fluorophore tetraphenylethylene [p 2219, col 1, para 2 to col 2, para 2] discussed above.
Response to Remarks: beginning on page 10 of Applicant’s response to rejections on the ground of non-statutory double patenting; Applicant in summary contends the instant claims are distinct from the cited references for the reasons stated in the response to rejections under 35 USC 103.
Applicant’s remarks are considered and found not convincing. The response to remarks regarding 35 USC 103 rejections is stated above, and will be repeated here.
Regarding the assertion that a person of ordinary skill in the art would not reasonably expect the probe of NIAIST to carry out all the functions of the claimed probe, as the probe in the claims interacts with the entire microbial surface including LPS, peptidoglycans, teichoic acids, polysaccharides and membrane lipids while the probe of NIAIST interacts with protein:
The claims do not recite a probe that interacts with the entire microbial surface including LPS, peptidoglycans, teichoic acids, polysaccharides and membrane lipids. Rather, the claims recite that the probe non-specifically interacts with a microorganism present in the microbiota.
Regarding the assertion that the NIAIST method would not be considered a microorganism detection method by one of ordinary skill in the art, and would not be able to provide a fingerprint of all the microorganisms present in a sample, as there is a significant leap from knowing a probe can bind proteins to expecting the probe can bind the majority of microorganisms in a sample, which is not supported by the disclosure of NIAIST:
The claims do not recite providing a fingerprint of all the microorganisms present in a sample, and do not recite the binding of the majority of microorganisms in a sample. The claims instead recite that the probe non-specifically interacts with a microorganism present in the microbiota.
Regarding the assertion that the claimed method is performed without protein extraction, and the absence of protein extraction in the NIAIST method is merely incidental and not a teaching of a method lacking protein extraction, wherein one of ordinary skill in the art would not reasonably expect such a method to work well for analyzing cell surfaces of intact microbiota:
The claims do note recite a method for analyzing cell surfaces of intact microbiota. The claims instead recite a method for monitoring changes in health status of an individual animal over time comprising a probe that non-specifically interacts with a microorganism present in the microbiota.
Regarding the assertion that any obviousness rejection would be overcome by secondary indicia of non-obviousness including solving a long-felt need, failure of others, and unexpected results, citing the long-felt need to discriminate complex microbiota to diagnose various conditions which others have failed to solve:
The claims do not recite a method comprising the discrimination of complex microbiota to diagnose various conditions.
Regarding Applicant’s allegations of unexpected results, Applicant alleges the present invention contains the unexpected high degree of accuracy of 91-94% (Example 6) and 100% (Example 7) to discriminate the microbiota of sleep disorder mice and mice with insufficient exercise, respectively, and that it is unexpected for the probe of NIAIST to not only bind proteins but other surface molecules as to accurately determine microbiota patterns:
MPEP 716.02(e) states the subject matter must be compared with the closest prior art to be effective to rebut a prima facie case of obviousness. As Applicant has not compared the proffered results to any prior art, Applicant has not satisfied the requirements of MPEP 716.02(e).
MPEP 716.02(b) states the burden is on Applicant to establish results are unexpected and significant, and that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance. The examples proffered by Applicant associated with the cited high accuracy are the result of comparisons within the same experiment. As Applicant has not compared these data to the prior art as stated above, it is unclear why these results are considered unexpected and significant against the prior art, and why these results are of practical significance. Therefore, Applicant has not satisfied the requirements of MPEP 716.02(b).
MPEP 716.02(d) states unexpected results must be commensurate in scope with the claimed invention. As the data in the Examples proffered by Applicant correspond to experiments using 6 probes with two types of microbiota-containing samples (and relevant controls), the results are not commensurate in scope with the claimed method that encompasses: (a) all probes comprising a cationic polymer comprising at least five primary amino groups in one molecule and having a weight-average molecular weight of 1,000 to 500,000; (b) the interaction of said probes with all microorganisms in all microbiota-containing samples; (c) identifying changes in health status of all animals; and (d) identifying changes in the health statuses of said animals of obesity, sleep disorder, and insufficient exercise. Therefore, Applicant has not satisfied the requirements of MPEP 716.02(d).
For these reasons, Applicant’s allegations of unexpected results are considered and found insufficient to rebut a prima facie case of obviousness.
Regarding the assertion that the aggregation-induced fluorophore of Wang does not teach the claimed fluorophore as Wang does not teach such fluorophores and tetraphenylethylenes covalently bonded to primary amino groups of cationic polymer that are designed to detect non-specific interactions with a variety of cell surface molecules, and that there is no motivation to combine the NIAIST probe with the Wang probe:
The claims do not recite the detection of non-specific interactions of a probe with a variety of cell surface molecules. The claims instead recite that the probe non-specifically interacts with a microorganism present in the microbiota. Additionally, the design intent of the claimed probe is not a claimed feature of the invention, but would be considered an intended use of the probe that does not structurally limit the probe being claimed in the method of claims 2-3. Regarding the function of the probe, as the probe of the combined method of NIAIST, Lai, Samanta and Wang is encompassed by the structural limitations of the probe in the claim as described in the rejection above, it is considered to have the function of detecting non-specific interactions with a variety of cell surface molecules, as MPEP 2112.01 states when the structure recited in the reference is substantially identical to that of the claimed, the claimed properties or functions are presumed to be inherent.
While Wang may not teach the binding of the fluorophore to the amino groups of a cationic polymer, NIAIST teaches a probe comprising (a) a cationic polymer comprising at least five primary amino groups in one molecule and having a weight average molecular weight of 1,000 to 500,000 and (b) an environment-sensitive fluorophore covalently bonded to a part of the primary amino group in the cationic polymer [claim 1]. As NIAIST teaches the architecture of the probe design and both the linkage sites and linkage types of an environmental-sensitive fluorophore to the probe, and Wang teaches an environmentally-sensitive fluorophore, it would have been obvious to modify the combined method of NIAIST, Lai and Samanta by using the fluorophore of Wang to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to modify the combined method of NIAIST, Lai and Samanta by using an aggregation-induced fluorophore because Wang teaches that aggregation-induced emission fluorophores can improve fluorescence quantum yield up to 3 orders of magnitude and can be used to detect biomolecule interactions.
Regarding the assertion that one of ordinary skill in the art would not reasonably expect the combination of NIAIST, Lai, Samanta and Wang to function in detecting non-specific interactions across the entire microbial surface in complex microbiota and discriminate microbial populations of animals with different health statuses:
The claims do not recite detecting non-specific interactions across the entire microbial surface in complex microbiota and discriminating microbial populations of animals with different health statuses.
Conclusion
Status of the Application:
Claims 1-5, 7-9 and 11-12 are pending.
Claims 1-5, 7-9 and 11-12 are rejected.
No claim is in condition for allowance.
THIS ACTION IS MADE FINAL. 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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/JOSEPH R SPANGLER/
Examiner
Art Unit 1656
/David Steadman/Primary Examiner, Art Unit 1656
Prosecution Insights