Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
The amended claim set filed 12 Aug 2025 is acknowledged. Claims 1-2, 4-10, 13-15, 17, 19, and 21-22 are currently pending. Of those, claims 1-2, 7, 13-14, and 19 are currently amended, no claims are new and no claims are withdrawn. Claims 3, 11-12, 16, 18, and 20 are cancelled. Claims 1-2, 4-10, 13-15, 17, 19, and 21-22 will be examined on the merits herein.
Response to Arguments
The Applicants’ arguments filed 12 Aug 2025 are acknowledged. For clarity, in this action, said arguments will be referred to as “Remarks” and the Non-Final Office Action mailed 12 May 2025 will be referred to as “NFOA.”
Objection(s) and Rejection(s) Withdrawn
The objections of claims 1 and 19 (NFOA par. 10) are withdrawn in view of claim amendments.
Rejections under 112(b) for claim 1 (par. 23, 24), claim 2 (par. 25), claim 13 (par. 26, 27, 28, 29), claim 19 (NFOA par. 30, 31) are withdrawn in view of claim amendments.
Rejections under 112(a) written description for claims 1 and dependent claims (NFOA par. 32-37, related to “therapeutic index”), claims 13 and dependent claims (NFOA par. 39-41, related to choosing populations where the ADME expression level is low and “therapeutic index”), claim 14 (NFOA par. 42-47, relating to subgenera of alternative compounds), claim 19 (NFOA par. 49-50, relating to “therapeutic index”) are withdrawn in view of claim amendments.
Rejections under 112(a) enablement for claims 1-2, 4-10, and 21-22 (NFOA par. 51-61) related to the terms “therapeutic index” and “effective and safe” and for claim 19 (NFOA par. 66-74) related to the terms “therapeutic index” and “metabolism” are withdrawn in view of claim amendments and arguments.
Rejections under 112(a) enablement for claim 7 (NFOA par. 63-65, relating to a lipid affinity-based capture technique to enrich proteins) is withdrawn in view of claim amendments.
New Objections
Claim Objections
Claim 1 is objected to because of the following informalities: the phrase “so that the second dose … having a therapeutic effect on the subject” is grammatically incorrect (subject-verb agreement error) and should read “has” instead. Appropriate correction is required.
Rejection(s) Maintained
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 § 101
Claims 13-15, and 17 remain rejected under 35 U.S.C. 101 because the claimed invention is directed to laws of nature and abstract ideas without significantly more for the reasons of record and the reasons herein.
Applicant argues (pg. 16-18) that
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Other arguments rely on this claim interpretation.
The arguments have been carefully considered but are not persuasive. Respectfully, applicant is incorrect about the administration step of claim 13. The administering step in claim 13 is an optional step that only occurs “when the enriched EV proteins or peptides indicate baseline expression” (see screenshot below). This was stated in the NFOA (par. 14): “The claim has been amended to recite an administration step, but this step is most broadly understood as being optional and only occurring when the enriched EV proteins or peptides indicate little upregulation or baseline expression.”
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In contrast to claim 13, in claim 1, the administration of the compound is a required step, with an additional optional limitation of modifying the second dose in certain ways “when a subject exhibits no upregulation”. Note that the required step is clearly separated from the optional limitation because the optional limitation is in an additional “wherein” clause and is separated by a new line.
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In contrast to claim 13, in claim 19, the administration of the compound is a required step, with an additional optional limitation of modifying the second dose in certain ways “when a subject exhibits no upregulation”. Note that the required step is clearly separated from the optional limitation because the optional limitation is in an additional “wherein” clause.
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The rejection is maintained for the reasons of record and the reasons herein.
New Rejection(s)
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-2, 4-10, 13-15, 17, 19 and 21-22 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 1, the “using” step recites the limitation “wherein the one or more ADME proteins comprise CYP3A4…” There is insufficient antecedent basis for this limitation in the claim, because previous uses refer to “one or more targeted ADME proteins”. This lack of antecedent basis, combined with the formatting so the phrase would limit a term that was defined several steps earlier, raises confusion about whether this limits the prior targeted ADME proteins that are referenced in multiple locations throughout the method, or whether this defines a new group of ADME proteins specifically used in the mass spectrometry quantification step. In the interest of compact prosecution, this will be interpreted as limiting the targeted ADME proteins used elsewhere in the method, in view of the case’s prosecution history, however the claims must still be amended to resolve the indefiniteness.
Also, the “when… baseline expression” phrase states “the first dose of the compound not having a therapeutic on the subject”, which has a word omitted after therapeutic. The specification teaches several phrases that could be used (therapeutic index, therapeutic effect, etc.), so the error is indefinite because the appropriate correction is not unambiguous and apparent. In the interest of compact prosecution, it appears the intended phrase was “therapeutic effect” in view of the arguments, however the claims must still be amended to resolve the indefiniteness.
This is also a rejection of dependent claims 2, 4-10 and 21-22 which depend from claim 1 and do not obviate these grounds of rejection.
Regarding claim 2, the claim requires a “step of facilitating the adjustment of a dose-response curve”. The word “facilitate” is not defined in the specification; near the time of filing Merriam-Webster defined the term as “to make easier: help bring about” (website captured 14 Apr 2020; PTO-892). One of ordinary skill in the art would not be able to determine what physical step(s) are claimed by a step of making the adjustment easier. It is unclear that any additional physical steps are required at all by this limitation, as the previous steps of measuring ADME proteins, assigning phenotypes, and administering a dosing regimen of the compound from claim 1 may be sufficient to meet the broadest possible interpretation of helping to bring about the adjustment. In the interest of compact prosecution, this limitation is interpreted as not being limiting, and claim 2 is interpreted as only requiring that the subject be a member of a treatment cohort.
Regarding claim 13, claim 13 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential steps, such omission amounting to a gap between the steps. See MPEP § 2172.01. The omitted steps are: steps capable of “profiling a subject's present drug response phenotype” as required to achieve the preamble. Instead, the steps presented are a method of administering a dose of a first compound that “achieves metabolic activity of the compound in the subject and a therapeutic effect”.
Also, the “identifying and quantifying” step recites “such ADME proteins comprise CYP3A4…” There is insufficient antecedent basis for this limitation in the claim, because previous uses refer to “one or more targeted ADME proteins”. This lack of antecedent basis, combined with the formatting so the phrase would limit a term that was defined several steps earlier, raises confusion about whether this limits the prior targeted ADME proteins that are referenced in multiple locations throughout the method, or whether this defines a new group of ADME proteins specifically used in the mass spectrometry quantification step. In the interest of compact prosecution, this will be interpreted as limiting the targeted ADME proteins used elsewhere in the method, in view of the case’s prosecution history, however the claims must still be amended to resolve the indefiniteness.
Also, the “administering” step recites “the second dose achieves metabolic activity of the compound in the subject”. One of ordinary skill would not be sure how to interpret whether or not this effect is achieved due to the unclear grammar. The claim is indefinite because the claim’s grammar states the metabolic activity is a property of the compound, but the broadest reasonable interpretation of the second dose (a chemical compound) is not limited to enzymes that are capable of performing metabolic activities.
This is also a rejection of dependent claims 14-15, and 17 which depend from claim 13 and do not obviate these grounds of rejection.
Regarding claim 17, the claim recites “the targeted one or more ADME proteins”, but claim 13 recites “to “one or more targeted ADME proteins” and “such ADME proteins”. There is insufficient antecedent basis for this limitation in the claim, because of the difference in the terms in combination with the use of two different ADME protein terms in claim 13.
Regarding claim 19, claim 19 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential steps, such omission amounting to a gap between the steps. See MPEP § 2172.01. The omitted steps are: steps capable of “determining drug metabolism” as required to achieve the preamble. Instead, the steps presented are a method of administering a dose of a compound based on the assigned phenotype for drug metabolism.
Also, the claims recite “one or more targeted … (ADME) proteins”, followed by “such ADME proteins” and “the targeted one or more ADME proteins” and “the targeted ADME protein”. There is insufficient antecedent basis for the later recitations of ADME proteins in the claim, because it is unclear whether they refer back to the original one or more targeted ADME proteins or whether they are defining new groups of proteins when considered in combination with the formatting, and because it is unclear whether “the targeted ADME protein” limits the claim to considering a single ADME protein instead of “one or more” as in the other recitations. In the interest of compact prosecution, these will all be interpreted as limiting the targeted ADME proteins used elsewhere in the method, in view of the case’s prosecution history, however the claims must still be amended to resolve the indefiniteness.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-2,4-10,13-15,17,19 and 21-22 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, 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, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP 2163 states:
The written description requirement is not necessarily met when the claim language appears in ipsis verbis in the specification. "Even if a claim is supported by the specification, the language of the specification, to the extent possible, must describe the claimed invention so that one skilled in the art can recognize what is claimed. The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement." Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002).
Thus, the written description requirement may be satisfied through disclosure of function and minimal structure when there is a well-established correlation between structure and function. In contrast, without such a correlation, the capability to recognize or understand the structure from the mere recitation of function and minimal structure is highly unlikely. In this latter case, disclosure of function alone is little more than a wish for possession; it does not satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (written description requirement not satisfied by merely providing "a result that one might achieve if one made that invention"); In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming a rejection for lack of written description because the specification does "little more than outline goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate").
Regarding claim 1 (and dependent claims), the claim has been amended to recite “a method for ensuring therapeutic effect of a compound” and assigning phenotypes so that “when enriched EV proteins or peptides indicate upregulated expression … it is indicative of … the first dose of the compound having a therapeutic effect on the subject, and when the enriched EV proteins or peptides indicate baseline expression… it is indicative of the first dose of the compound not having a therapeutic [effect] on the subject”, and the intended outcome that “when a subject exhibits no upregulation of the targeted ADME protein” then administering a second dose of the compound “so that the second dose achieves metabolic activity of the compound in the subject and having a therapeutic effect on the subject”. The specification has not re-defined the term “therapeutic effect” relative to the accepted definition of “therapeutic”, which is defined at Merriam-Webster as “(1) of or relating to the treatment of disease or disorders by remedial agents or methods : curative, medicinal; (2) having a beneficial effect on the body or mind; (3) producing a useful or favorable result or effect” (website captured 15 Sep 2019; PTO-892).
Applicant pointed to [0102-0107] of the Pre-Grant publication as support for these limitations, which cite support to “the data set forth herein” to show “upregulated expression of the targeted ADME protein(s) is indicative of the at least one dose of the compound being within the therapeutic index of the compound for the subject (i.e. the subject experiencing a therapeutic response/the dose being a therapeutically effective dose).” [0102].
However, the specification does not teach any working examples of the method as claimed and the data presented does not provide support for the limitations. The data explicitly contradicts the claimed statements when the ADME protein is upregulated. The specification reduces to practice a specific method of isolating EVs (“EVTRAP”) and quantifying CYP3A4 via parallel reaction monitoring mass spectrometry [0088-0092], and demonstrated that rifampicin, “a well-known inducer” was administered to hepatocyte lysate [0094], led to the expected upregulation of CYP3A4 levels in the EVs [0094-0095]. There is no data from any drug being administered in vivo. The specification does not show that rifampicin (an antibiotic) has any therapeutic (i.e. curative, beneficial) effect in non-infected hepatocyte lysate, nevertheless the ADME protein (CYP3A4) level was increased despite the lack of therapeutic effect. The data relied upon for support explicitly contradicts the claim limitation that “enriched EV proteins or peptides indicate upregulated expression … is indicative of … the first dose of the compound having a therapeutic effect on the subject” and cannot be considered to provide support.
When the ADME protein is at baseline, the cited paragraphs do not teach how to modify the second dose if the ADME composition is at baseline in order to achieve metabolic activity and a therapeutic dose. Para. [0104 and 0107] (from Pre-Grant Publication) assert that “the dose can be modified (e.g., increased or decreased in concentration and/or modified in timing and/or number of doses administered) in the interest of achieving metabolic activity of the compound in the subject and a therapeutic effect” [0104] and that “where a subject exhibits little or no activity/upregulation of the targeted ADME protein/peptide (as compared to baseline) following administration of a first dose of a compound, the method can further comprise administering a second, adjusted dose of the compound to the subject (e.g., an increased dose concentration or dosage amount of the compound) and/or adjusting dose frequency to facilitate a therapeutic response in the subject” [0107].
One of ordinary skill in the art would not consider these two sentences (or the section of [0102-0107] as a whole, or the specification as a whole) to be a detailed description of the claimed method. The specification does not reduce to practice any examples of increasing or modifying the second dose to achieve a therapeutic effect. The specification does not provide any calculations or examples of how to perform this step using simplified data. The specification does not even explain what steps a person of ordinary skill in the art should take to determine how the second dose should be modified to achieve the claimed effects of “achieving metabolic activity of the compound in the subject and having a therapeutic effect on the subject” and “ensuring a therapeutic effect.” The specification is not required to disclose each of these features, but in combination, their lack makes it clear that the specification does not provide distinguishing identifying characteristics for the claimed method.
The art at the time of filing (Rowland et al.; WO-2019051546-A1; made of record in PTO-892 mailed 23 Nov 2022) teaches a similar method of selectively isolating EVs from a biofluid sample [0136-0137], enriching for specific EV populations [0136-0137], and extracting EV proteins and quantifying CYP3A4 levels [0157, 0065]. Rowland teaches that EV levels of both CYP3A4 mRNA and protein were highly correlated with midazolam apparent oral clearance (CL/F) [0170-0173, Figure 4A-B]. Rowland also teaches that CYP3A4 mRNA levels and protein levels within EVs are highly correlated with each other [0170-0173; Figure 4D]; in combination with the data demonstrating that mRNA levels are upregulated after rifampicin administration [0180-0182, Figures 6-7], this data demonstrates both that CYP3A4 mRNA levels are upregulated in response to drug metabolism and that the CYP3A4 protein levels are present in the EVs at increased levels when at least a therapeutically effective dose of a drug is administered to a subject, relative to a baseline CYP3A4 protein level before the drug administration. Rowland teaches administering a dose of the drug midazolam that varies based on the assigned phenotype, but unlike the claimed method, Rowland teaches that increased CYP3A4 levels result in administration of increased midazolam dosage (not the same levels as in the claims), and that low CYP3A4 levels result in reduced midazolam levels (not increased in the claims) [0220]. Rowland teaches that this is done to achieve a consistent exposure of the drug between individuals [0220], but that this midazolam example can only be determined because of the data demonstrating the relationship between exosome CYP3A4 levels and the dose required to standardize exposure [0222]. Similar studies would need to be conducted for other drugs to determine the relevant thresholds [0222-0223]. Rowland teaches that administering the wrong dosage (as in the claimed method where the dose should be increased rather than decreased as taught in Rowland) does not result in a therapeutic effect: “Inadequate exposure to a drug may result in a lack of efficacy ("therapeutic failure"), while excessive exposure increases the risk of toxicity and reduces tolerability.” [0004].
When evaluating the specification in the context of the prior art at the time of filing, one having ordinary skill in the art at the time of filing would have concluded that the specification failed to demonstrate possession of “a method for ensuring therapeutic effect of a compound” and assigning phenotypes so that “when enriched EV proteins or peptides indicate upregulated expression … it is indicative of … the first dose of the compound having a therapeutic effect on the subject, and when the enriched EV proteins or peptides indicate baseline expression… it is indicative of the first dose of the compound not having a therapeutic [effect] on the subject”, and the intended outcome that “when a subject exhibits no upregulation of the targeted ADME protein” then administering a second dose of the compound “so that the second dose achieves metabolic activity of the compound in the subject and having a therapeutic effect on the subject”. Instead, the specification only present a wish for possession of steps with the claimed functions, which the MPEP and courts have affirmed lacks written description. Therefore, claim 1 is rejected as lacking written description, and claims 2, 4-10, and 21-22 are rejected for depending from claim 1 and not obviating this ground of rejection.
Regarding claim 2, the claim has been amended to recite the functional limitation “further comprising the step of facilitating the adjustment of a dose-response curve”. Applicant pointed to [0105] of the Pre-Grant publication as support.
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While the specification states that the method can be used to “facilitate the adjustment of dose-response curves”, one of ordinary skill in the art would not consider this paragraph to be a detailed description of the claimed method. The specification does not reduce to practice any examples of performing this “facilitation”. The specification does not provide any explanations of how to perform this step using simplified data. The specification does not explain what steps should be taken, or even explain the intended outcome of how the dose-response curve would be modified to achieve the goal of “otherwise determining effective and safe dosing regimens for a particular compound” as in [0101] or “ensuring therapeutic effect” as in claim 1’s preamble. The specification is not required to disclose each of these features, but in combination, their lack makes it clear that the specification does not provide distinguishing identifying characteristics for the claimed method.
The state of the art is described above in the rejection of claim 1, but in particular, Rowland teaches that the midazolam example can only be determined because of the data demonstrating the relationship between exosome CYP3A4 levels and the dose required to standardize exposure [0222]. Similar studies would need to be conducted for other drugs to determine the relevant thresholds [0222-0223].
When evaluating the specification in the context of the prior art at the time of filing, one having ordinary skill in the art at the time of filing would not have concluded that the specification demonstrated possession of a “step of facilitating the adjustment of a dose-response curve”, but instead only presented a wish for possession of steps with that function, which the MPEP and courts have affirmed lacks written description. Therefore, claim 2 is rejected for failing to demonstrate possession of the claimed invention.
Regarding claim 13, like claim 1, claim 13 teaches the same sample processing and phenotype assignment steps and has been amended to recite that the steps conclude in an optional step where “when the enriched EV proteins or peptides indicate baseline expression of the targeted one or more ADME proteins” “administering a second dose of the first compound, the second dose comprising an increased concentration of the first compound, an increased amount of the first compound, or being administered at a higher frequency than the first dose of the first compound so that the second dose achieves metabolic activity of the compound in the subject and a therapeutic effect”. Like claim 1, applicant pointed to [0102-0103] as providing support. One of ordinary skill in the art would not consider these paragraphs, and the specification as a whole, to be a detailed description of the method step of administering a modified second dose to achieve a therapeutic effect, for the same reasons laid out in claim 1. When evaluating the specification in the context of the prior art at the time of filing, one having ordinary skill in the art at the time of filing would have concluded that the specification failed to demonstrate possession of the claimed method. Instead, the specification only presents a wish for possession of steps with the claimed functions, which the MPEP and courts have affirmed lacks written description. Therefore, claim 13 is rejected as lacking written description and claims 14-15, and 17 are rejected for depending from claim 1 and not obviating this ground of rejection.
Regarding claim 19, like claim 1, claim 19 teaches the same method steps and has been amended to recite assigning phenotypes so that “when enriched EV proteins or peptides indicate upregulated expression … it is indicative of … the first dose of the compound having a therapeutic effect on the subject, and when the enriched EV proteins or peptides indicate baseline expression… it is indicative of the first dose of the compound not having a therapeutic effect on the subject”. Like claim 1, applicant pointed to [0102-0103] as providing support. However, as discussed in claim 1, the specification explicitly provides data demonstrating that a drug administration that upregulates expression of an ADME protein (CYP3A4) does not correspond to a therapeutic effect, and the art at the time of filing indicates that a therapeutic effect is not predictably correlated with upregulated ADME proteins because Rowland teaches that subjects with upregulated CYP3A4 levels should be administered reduced dosages to avoid toxicity, as cited above. When evaluating the specification in the context of the prior art at the time of filing, one having ordinary skill in the art at the time of filing would have concluded that the specification failed to demonstrate possession of the claimed method because the only data presented in the specification contradicts the claim limitation. Therefore, claim 19 is rejected as lacking written description.
Claims 1-2, 4-10, and 21-22 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for using CYP3A4 levels to dose midazolam in the manner described in Rowland et al., does not reasonably provide enablement for “ensuring an therapeutic effect” and administering a dose “so that the second dose achieves metabolic activity of the compound in the subject and having a therapeutic effect on the subject,” for other drugs, and other dosage plans. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The factors to be considered in determining whether a disclosure would require undue experimentation include: (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. In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01. Although all factors were considered, the Wands factors that were most relevant for this decision are discussed in detail below.
The breadth of the claims: Claim 1 (and its dependent claims)require that the method accomplish the intended use of “ensuring a therapeutic effect of a compound in a subject”, by performing the steps of establishing the baseline expression of specific ADME proteins (CYP3A4, CYP2E1, CYP2A, CYP1A1/2, or CYP4B), then isolating extracellular vesicles (EVs) and EV proteins from “a biofluid sample of a subject having received at least one dose of the compound”, measuring the levels of the specific ADME proteins and comparing with the baseline level to determine whether the ADME proteins are upregulated or at baseline, and assigning a corresponding phenotype to the subject. Then, the claim requires the step of “administering a dosing regimen of the compound… so that the second dose achieves metabolic activity of the compound in the subject and having a therapeutic effect on the subject.” Also, the claim has been amended to require that “when enriched EV proteins or peptides indicate upregulated expression … it is indicative of … the first dose of the compound having a therapeutic effect on the subject, and when the enriched EV proteins or peptides indicate baseline expression… it is indicative of the first dose of the compound not having a therapeutic [effect] on the subject”.
Claim 13 is a method “for profiling a subject's present drug response phenotype”, but whose final step is “administering a second dose of the first compound, the second dose comprising an increased concentration of the first compound, an increased amount of the first compound, or being administered at a higher frequency than the first dose of the first compound so that the second dose achieves metabolic activity of the compound in the subject and a therapeutic effect, when the enriched EV proteins or peptides indicate baseline expression of the targeted one or more ADME proteins”, so it appears that success at the method requires being able to administer the second dose based on the phenotype as claimed. Claim 13 has the same steps as claim 1, except that the final step of administering a second dose only occurs when the ADME proteins are at baseline level.
Claim 19 is a method “for determining drug for determining drug metabolism” but whose final step is “administering a second dose of the compound, the second dose based on the assigned phenotype for drug metabolism”, so it appears that success at the method requires being able to administer the second dose based on the phenotype as claimed. Claim 19 has the same steps as claim 1, except that “the step of isolating is performed via lipid affinity-based capture using a device comprising a plurality of microspheres having surfaces coated or modified with a combination of at least one hydrophilic group and at least one hydrophobic group;”.
To accomplish these methods (or the methods of dependent claims) with a reasonable expectation of success, ADME protein levels must be a valid proxy for a drug having a therapeutic effect for claims 1 and 19 (and dependent claims), and also one of ordinary skill in the art must be able to use the ADME protein level phenotype to modify the second dose with a reasonable expectation of achieving “metabolic activity of the compound in the subject and having a therapeutic effect on the subject” in claims 1 and 13 (and dependent claims) or successful therapy in claim 19.
The specification has not re-defined the term “therapeutic effect” relative to the accepted definition of “therapeutic”, which is defined at Merriam-Webster as “(1) of or relating to the treatment of disease or disorders by remedial agents or methods : curative, medicinal; (2) having a beneficial effect on the body or mind; (3) producing a useful or favorable result or effect” (website captured 15 Sep 2019; PTO-892).
The state of the prior art and the level of predictability in the art: The art at the time of filing (Rowland et al.; WO-2019051546-A1; made of record in PTO-892 mailed 23 Nov 2022) teaches a similar method of selectively isolating EVs from a biofluid sample [0136-0137], enriching for specific EV populations [0136-0137], and extracting EV proteins and quantifying CYP3A4 levels [0157, 0065]. Rowland teaches that EV levels of both CYP3A4 mRNA and protein were highly correlated with midazolam apparent oral clearance (CL/F) [0170-0173, Figure 4A-B]. Rowland also teaches that CYP3A4 mRNA levels and protein levels within EVs are highly correlated with each other [0170-0173; Figure 4D]; in combination with the data demonstrating that mRNA levels are upregulated after rifampicin administration [0180-0182, Figures 6-7], this data demonstrates both that CYP3A4 mRNA levels are upregulated in response to drug metabolism and that the CYP3A4 protein levels are present in the EVs at increased levels when at least a therapeutically effective dose of a drug is administered to a subject, relative to a baseline CYP3A4 protein level before the drug administration. Rowland teaches administering a dose of the drug midazolam that varies based on the assigned phenotype, but unlike the claimed method, Rowland teaches that increased CYP3A4 levels result in administration of increased midazolam dosage (not the same levels as in the claims), and that low CYP3A4 levels result in reduced midazolam levels (not increased in the claims) [0220]. Rowland teaches that this is done to achieve a consistent exposure of the drug between individuals [0220], but that this midazolam example can only be determined because of the data demonstrating the relationship between exosome CYP3A4 levels and the dose required to standardize exposure [0222]. Similar studies would need to be conducted for other drugs to determine the relevant thresholds [0222-0223]. Rowland teaches that administering the wrong dosage does not result in an effective and safe therapeutic effect; “Inadequate exposure to a drug may result in a lack of efficacy ("therapeutic failure"), while excessive exposure increases the risk of toxicity and reduces tolerability.” [0004].
Rowland’s teaching that the relationship between CYP protein levels and drug effects needs to be determined on a drug-by-drug basis is corroborated by the art at the time of filing. Cho et al. (2017; made of record in IDS filed 1 Jun 2021) teaches that different CYP proteins react differently to the same compound dosage; administration of ethanol increases the level of CYP2E1, CYP2A, CYP1A1/2, and CYP4B in circulating EVs, but does not increase the level of CYP4A (Figure 1E and legend, Abstract). Pal et al. (2006; PTO-892) teaches that different drugs interact with the same CYP protein in different ways; clarithromycin and refabutin inhibit CYP3A4, but rifampicin induces CYP3A4 (par. bridging pg. 324-325). Therefore, the art teaches that the expression level of one or more selected ADME proteins from CYP3A4, CYP2E1, CYP2A, CYP1A1/2, or CYP4B will not reliably be upregulated by a drug within the therapeutic index, because not all CYP proteins are upregulated by each drug and because a specific drug might upregulate or inhibit the claimed CYP proteins.
Rowland teaches that the CYP protein-drug relationship must be determined for each drug and CYP protein, and the art confirms the high level of unpredictability. If one of ordinary skill performed the method and found baseline CYP protein levels, it is not possible to determine whether a subject is showing baseline CYP protein levels because the drug is below the dose required to upregulate the protein, because the drug inhibits the protein rather than upregulating it, or because the drug does not affect that particular CYP protein. Even if it were possible to know that the CYP protein is at baseline because the drug’s dosage were too low, administering an increased concentration, amount, or frequency of the compound will not reliably result in a dosage within a therapeutic effect because it may also result in an overdose or because the drug does not have any therapeutic effect like with ethanol. Therefore, administering an increased dose will not with a reasonable expectation of success result in a dose that is has a therapeutic effect or that is successful.
The amount of direction provided by the inventor and the existence of working examples: The specification does not teach any working examples of the method as claimed. The specification reduces to practice a specific method of isolating EVs (“EVTRAP”) and quantifying CYP3A4 via parallel reaction monitoring mass spectrometry [0088-0092], and demonstrated that rifampicin, “a well-known inducer” was administered to hepatocyte lysate [0094], led to the expected upregulation of CYP3A4 levels in the EVs [0094-0095]. The specification does not show that rifampicin (an antibiotic) has any therapeutic (i.e. curative, beneficial) effect in non-infected hepatocyte lysate, nevertheless the ADME protein (CYP3A4) level was increased despite the lack of therapeutic effect. The data presented explicitly contradicts the claim limitation that “enriched EV proteins or peptides indicate upregulated expression … is indicative of … the first dose of the compound having a therapeutic effect on the subject” and shows lack of enablement for the method.
There is no data from any drug being administered in vivo. The specification does not reduce to practice any examples of assigning a phenotype to a subject or administering a dosage of the compound (rifampicin) to the subject based on that phenotype. The specification does not reduce to practice any measurements of CYP2E1, CYP2A, CYP1A1/2, or CYP4B, so it has not shown that all claimed CYP proteins are upregulated together, nor has it provided an example explaining how to determine the subject’s phenotype when some proteins are upregulated and others are not. The specification has not reduced to practice any examples that determine how much to increase the compound’s concentration, amount, or frequency when the ADME protein is at baseline to result in a dosage that is results in a therapeutic effect.
The rest of the specification, other than what was reduced to practice, also does not provide the necessary guidance to overcome the unpredictability in the art. [0103] alleges that “lack of upregulated expression … is indicative of the compound dosage is not having a therapeutic effect on the subject”, and [0104] states “the dose can be modified (e.g., increased or decreased in concentration and/or modified in timing and/or number of doses administered) in the interest of achieving metabolic activity of the compound in the subject and a therapeutic effect”, but this does not explain how one of ordinary skill in the art should actually perform the modification to result in a therapeutic effect rather than an higher-than-necessary dose, and does not explain how drugs without therapeutic effects like ethanol would become therapeutic. Similarly, [0078] states “This EV proteome analysis can then be leveraged to determine drug efficacy and dose ranging for pharmaceutical or dosing studies, or in point of care or otherwise clinical setting for profiling a subject's current drug response in an effort to facilitate safe and effective therapeutic treatment”, but does not teach how this step of determining dose ranges is performed.
Administering an increased dose or frequency of the compound will not necessarily result in a dosing regimen within the therapeutic index; the specification teaches that “[drug] metabolism can result in toxicity, for instance by formation of toxic or biologically reactive metabolites,… [and] an average dosage can be possibly toxic to a poor metabolizer because that patient is not efficient in detoxifying and excreting drugs” [0007 and 0009]. Therefore, if the average, initial dosage can be toxic to a poor metabolizer (whose phenotype is indicated by little or no upregulation of the ADME protein), it is hard to see how increasing the dosage would bring the dosing regimen into the therapeutic index as required by the claim.
The quantity of experimentation needed to make or use the invention: The standard of an enabling disclosure is not the ability to make and test if the invention works but one of the ability to make and use with a reasonable expectation of success and without undue experimentation. A patent is granted for a completed invention, not the general suggestion of an idea (MPEP 2164.03 and Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1325-26 (Fed. Cir. 2004). The instant specification is not enabling because one cannot follow the guidance presented therein, or within the art at the time of filing, and practice the claimed method without first making a substantial inventive contribution.
Given the specific evidence from the specification and the art (Cho) that increased ADME proteins are not indicative of a drug having a therapeutic effect, there is no amount of experimentation that can enable this limitation.
Given that the nature of the invention is in vivo ensuring an effective and safe therapeutic effect and administering a dosing regimen within the therapeutic index, a person having ordinary skill in the art would have to follow the teachings of Rowland to perform additional experimentation for each drug and CYP protein of interest in order to determine whether a relationship exists between the dosage and the CYP protein’s expression, and then to determine how to use that relationship in order to administer a dosage with a therapeutic effect (claim 1, dependent claims) or with success (claims 13, 19, dependent claims). This would require numerous further in vivo experiments in human clinical trials or in animal models that are predictive of the subject’s drug response for a representative number of all possible drugs, in order to demonstrate the invention could be used with a reasonable expectation of success.
The amount of experimentation required for enabling guidance, commensurate in scope with what is claimed, goes beyond what is considered ‘routine' within the art, and constitutes undue further experimentation in order to use the method with a reasonable expectation of success. Therefore, claims 1-2,4-10,13-15,17,19 and 21-22 are rejected under 35 U.S.C. §112(a) or 35 U.S.C. §112, first paragraph, for failing to meet the enablement requirement.
Conclusion
No claims are allowed.
The request for an interview “if the Examiner determines that there are any further objections or rejections that would prevent all claims of the present Application from proceeding to allowance” (Remarks pg. 26), is respectfully declined. Examination has not identified any specific issues that would be best clarified via discussion, and where a productive interview would not require the applicant to have reviewed this written action in advance of the interview. See MPEP 713.01.IV.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/AMELIA NICOLE DICKENS/Examiner, Art Unit 1645
/GARY B NICKOL/Supervisory Patent Examiner, Art Unit 1645