DETAILED ACTION
Disposition of Claims
Claims 1-20 were pending. Claims 2, 4, 6-8, 15-16, and 20 have been cancelled. Amendments to claims 1, 3, 5, 9, 12-13, and 17-18 are acknowledged and entered. Claims 1, 3, 5, 9-14, and 17-19 will be examined on their merits.
Examiner’s Note
All paragraph numbers (¶) throughout this office action, unless otherwise noted, are from the US PGPub of this application US20240150854A1, Published 05/09/2024.
Applicant is encouraged to utilize the new web-based Automated Interview Request (AIR) tool for submitting interview requests; more information can be found at https://www.uspto.gov/patent/laws-and-regulations/interview-practice.
Optional Authorization to Initiate Electronic Communications
The Applicant’s representative may wish to consider supplying a written authorization in response to this Office action to correspond with the Examiner via electronic mail (e-mail). This authorization is optional on the part of the Applicant’s representative, but it should be noted that the Examiner may not initiate nor respond to communications via electronic mail unless and until Applicant’s representative authorizes such communications in writing within the official record of the patent application. A sample authorization is available at MPEP § 502.03, part II. If Applicant’s representative chooses to provide this authorization, please ensure to include a valid e-mail address along with said authorization.
Response to Arguments
Applicant's arguments filed 07/01/2026 regarding the previous Office action dated 04/02/2026 have been fully considered. If they have been found to be persuasive, the objection/rejection has been withdrawn below. Likewise, if a rejection/objection has not been recited, said rejection/objection has been withdrawn. If the arguments have not been found to be persuasive, or if there are arguments presented over art that has been utilized in withdrawn rejections but utilized in new rejections, the arguments will be addressed fully with the objection/rejection below.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 06/10/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Notably, the disclosure statement filed lists a Search Report. The listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
Claim Rejections - 35 USC § 112(b); Second Paragraph
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
(Rejection withdrawn.) The rejection of Claims 1, 3, 5, and 17 and dependent claims 2, 4, 6-16, and 18-19 thereof under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of the amendments to the claims.
(Rejection withdrawn.) The rejection of Claims 1, 3, 5, and 17 and dependent claims 2, 4, 6-16, and 18-19 thereof under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of the amendments to the claims.
(Rejection withdrawn.) The rejection of Claim 12 and dependent claim 13 thereof under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of the amendments to the claims.
(Rejection withdrawn.) The rejection of Claim 14 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of the amendments to the claims.
(Rejection withdrawn.) The rejection of Claim 16 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of the cancellation of said claim.
(Rejection withdrawn.) The rejection of Claim 18 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of the amendments to the claims.
(New rejection – necessitated by amendment.) Claim 1 and dependent claims 3, 5, and 9-14 thereof are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 has been amended to recite the following: “(d) detecting using a multiplex real-time PCR:
(i) a first Mpox virus nucleic acid sequence in the nucleic acids of part (c); and
(ii) at least one second nucleic acid sequence that serves as a positive or negative control in the nucleic acids of part (c).”
It is unclear what structural or functional characteristics are required for a nucleic acid sequence to constitute the recited “first Mpox virus nucleic acid sequence.” The claim does not require that the first nucleic acid sequence be specific to Mpox virus, distinguish Mpox virus from other orthopoxviruses, correspond to any particular Mpox gene or genomic region, or otherwise define a relationship between detection of the recited sequence and the claimed determination of the presence of Mpox in the subject. Accordingly it is unclear whether any sequence occurring within a Mpox genome satisfies the limitation, including a sequence that may be present in other orthopoxviruses, or whether the sequences must provide diagnostically specific detection of Mpox virus.
The scope of the recited “at least one second nucleic acid sequence that serves as a positive or negative control” is also unclear. The claim does not identify what process or result is being controlled or monitored by the second nucleic acid sequence. For example, the language does not distinguish between a control for specimen adequacy, nucleic acid extraction, amplification, PCR inhibition, assay performance, or contamination. The claim further does not define the relationship required between the second nucleic acid sequence and the first Mpox virus nucleic acid sequence within the multiplex RT-PCR assay. In addition, the recitation that a nucleic acid “serves as a…negative control” is unclear because a negative control may involve the absence of a target nucleic acid rather than the presence of a second nucleic acid sequence.
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant claim 1 is rejected on the grounds of being indefinite. Claims 3, 5, and 9-14 are also rejected since they depend from claim 1, but do not remedy these deficiencies of claim 1.
(New rejection – necessitated by amendment.) Claim 17 and dependent claims 18-19 thereof are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 17 is drawn to a system for detecting a presence of a Mpox virus in a sample from a subject comprising:
(a) a component for isolation of the Mpox virus from a solid substrate comprising the sample using a multi-well procedure, wherein the solid substrate is a dry swab;
(b) a component for purification of an Mpox virus nucleic acid sequence from the sample of step (a) using a multi-well procedure;
(c) a component for PCR amplification of the Mpox virus nucleic acid sequence; and
(d) a component to output results indicating a presence or absence of the Mpox virus nucleic acid sequence in the sample of part (a).
The scope of claim 17 is unclear because the claims does not define what is required for a nucleic acid sequence to constitute an “Mpox virus nucleic acid sequence” in the context of a system expressly recited as detecting the presence of Mpox virus. In particular, it is unclear whether the recited “Mpox virus nucleic acid sequence” encompasses any nucleic acid sequence occurring within the Mpox viral genome, including a sequence that may also occur in other Orthopoxviruses, or whether the recited sequence must be sufficiently specific to Mpox virus such that detection of the sequence permits the claimed system to determine the presence or absence of Mpox virus in the sample. These interpretations result in materially different scopes of the claimed system.
This ambiguity extends through each of parts (b)-(d). Part (b) recites a component for purification of “an Mpox virus nucleic acid sequence” from the sample, but it is unclear whether this limitation requires a component that selectively purifies an Mpox virus specific nucleic acid sequence from other nucleic acids present in the sample, or merely a conventional nucleic acid purification component that non-selectively purifies nucleic acids from a sample that may contain a sequence also occurring in Mpox virus. The latter interpretation would encompass purification of nucleic acids generally and would not require the purification component itself to distinguish Mpox nucleic acid from other viral or host nucleic acids.
Part (c) subsequently requires PCR amplification of “the Mpox virus nucleic acid sequence,” but does not resolve which of these interpretations is intended. Under one reasonable interpretation, amplification of any sequence occurring within an Mpox genome would satisfy the limitation. Under another interpretation, the amplified sequence must permit specific identification of Mpox virus. The claim provides no limitation establishing which degree of specificity is required.
The ambiguity is particularly material when part (d) is considered together within the preamble of claim 17. The preamble defines the claimed system as being “for detecting a presence of Mpox virus,” whereas part (d) merely requires output of results indicating the presence or absence of “the Mpox virus nucleic acid sequence.” Detection of a nucleic acid sequence that occurs in Mpox virus does not necessarily establish the presence of Mpox virus if that sequence is also present in another virus, including another Orthopoxvirus. Accordingly, it is unclear whether the output component must produce a result that specifically indicates the presence or absence of Mpox virus, or whether the limitation is satisfied by output indicating the presence or absence of any nucleic acid sequence that happens to be found within the Mpox genome, irrespective of whether that sequence permits identification of the Mpox virus.
The specification fails to resolve this uncertainty because it describes both nucleic acid sequences associated with Orthopoxviruses and more particularly define viral targets used for diagnostic detection. Accordingly, the claim language leaves the metes and bounds unclear.
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant claim 17 is rejected on the grounds of being indefinite. Claims 18-19 are also rejected since they depend from claim 17, but do not remedy these deficiencies of claim 17.
Claim Rejections - 35 USC § 112(d); Fourth Paragraph
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
(Rejection withdrawn.) The rejection of Claim 3 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, is withdrawn in light of the amendments to the claims.
Claim Interpretation
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
Claim 1 is drawn to a method for detecting a presence of a monkeypox (Mpox) virus in a subject comprising:
(a) obtaining a sample from at least one skin lesion site from the subject on a solid substrate, wherein the solid substrate is a dry swab;
(b) isolating Mpox virions from the dry swab using a multi-well extraction procedure;
(c) extracting nucleic acids from the isolated Mpox virions using a multi-well viral nucleic acid purification procedure;
(d) detecting using a multiplex real-time PCR:
(i) a first Mpox virus nucleic acid sequence in the nucleic acids of part (c); and
(ii) at least one second nucleic acid sequence that serves as a positive or negative control in the nucleic acids of part (c).
Further limitations on the method of claim 1 are wherein the first Mpox virus nucleic acid sequence comprises a sequence of the E9L gene of the Mpox virus (claim 3), wherein the second nucleic acid comprises a sequence of the human RNase P gene and/or a vaccinia virus (claim 5), further comprising multiplex qPCR for at least two of the E9L gene, the human RNase P gene or the vaccinia virus sequences (claim 14); wherein the dry swab is a synthetic tip swab with an aluminum shaft or a synthetic tip swab with a plastic shaft (claim 9); wherein the step of obtaining the sample comprises self- collection of the sample by the subject (claim 10); further comprising purification of the first nucleic acid sequence by binding the nucleic acid to silica beads (claim 11); wherein samples from two or more subjects are processed simultaneously (claim 12), wherein samples from 20 or more subjects are processed simultaneously (claim 13).
The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The following is a quotation of pre-AIA 35 U.S.C. 112, sixth paragraph:
An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. The broadest reasonable interpretation of a claim element (also commonly referred to as a claim limitation) is limited by the description in the specification when 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is invoked.
As explained in MPEP § 2181, subsection I, claim limitations that meet the following three-prong test will be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph:
(A) the claim limitation uses the term “means” or “step” or a term used as a substitute for “means” that is a generic placeholder (also called a nonce term or a non-structural term having no specific structural meaning) for performing the claimed function;
(B) the term “means” or “step” or the generic placeholder is modified by functional language, typically, but not always linked by the transition word “for” (e.g., “means for”) or another linking word or phrase, such as “configured to” or “so that”; and
(C) the term “means” or “step” or the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.
Use of the word “means” (or “step”) in a claim with functional language creates a rebuttable presumption that the claim limitation is to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites sufficient structure, material, or acts to entirely perform the recited function.
Absence of the word “means” (or “step”) in a claim creates a rebuttable presumption that the claim limitation is not to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is not interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites function without reciting sufficient structure, material or acts to entirely perform the recited function.
Claim limitations in this application that use the word “means” (or “step”) are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action. Conversely, claim limitations in this application that do not use the word “means” (or “step”) are not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action.
This application includes one or more claim limitations that do not use the word “means,” but are nonetheless being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, because the claim limitation(s) uses a generic placeholder that is coupled with functional language without reciting sufficient structure to perform the recited function and the generic placeholder is not preceded by a structural modifier. Such claim limitation(s) is/are: “a component for” recited numerous times in claim 17.
Because this/these claim limitation(s) is/are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, it/they is/are being interpreted to cover the corresponding structure described in the specification as performing the claimed function, and equivalents thereof.
If applicant does not intend to have this/these limitation(s) interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, applicant may: (1) amend the claim limitation(s) to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph (e.g., by reciting sufficient structure to perform the claimed function); or (2) present a sufficient showing that the claim limitation(s) recite(s) sufficient structure to perform the claimed function so as to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph.
Claim 17 is drawn to a system for detecting a presence of a Mpox virus in a sample from a subject comprising:
(a) a component for isolation of the Mpox virus from a solid substrate comprising the sample using a multi-well procedure, wherein the solid substrate is a dry swab;
(b) a component for purification of an Mpox virus nucleic acid sequence from the sample of step (a) using a multi-well procedure;
(c) a component for PCR amplification of the Mpox virus nucleic acid sequence; and
(d) a component to output results indicating a presence or absence of the Mpox virus nucleic acid sequence in the sample of part (a).
Further limitations on the system of claim 17 are wherein the system is further comprising a component for self-collection of the sample by the subject (claim 18); and wherein at least one of the components is controlled by a computer (claim 19).
Claim Rejections - 35 USC § 112(a); First Paragraph
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
(Rejection withdrawn.) The rejection of Claims 1-20 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement is withdrawn in light of the amendments to the claims and applicant arguments.
(New rejection – necessitated by amendment.) Claims 1, 3, 5, 9-14, and 17-19 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 the disclosed assays using the VAC1 primer/probe set directed to the E9L gene, the disclosed RNAse P primer/probe control, vaccina controls, and the disclosed multi-well extraction and nucleic acid purification procedures, does not reasonably provide enablement for the substantially broader scope of Mpox nucleic acid targets and control nucleic acid sequences 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 legal considerations that govern enablement determinations pertaining to undue experimentation have been set forth in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). The factors to be considered include: (1) the breadth of the claims; (2) the nature of the invention; (3) the state of the prior art; (4) the level of one of ordinary skill; (5) the level of predictability in the art; (6) the amount of direction provided by the inventor; (7) the existence of working examples; and (8) the quantity of experimentation needed to make or use the invention based on the content of the disclosure. The factors are considered as a whole in determining whether any necessary experimentation would have been undue.
Nature of the invention and breadth of the claims. The claimed invention is directed to methods and systems for detecting the presence of Mpox virus in a subject using viral isolation, nucleic acid purification, and PCR detection, namely wherein the viral sample is acquired using a lesion site swab and isolating any Mpox virions using a multi-well extraction procedure, and detection using a real-time PCR multi-well system.
The specification describes a considerably more narrow and defined assay, wherein the target assay employs the VAC1 primer/probe system directed to the E9L gene, while the disclosed human control uses an RNase P primer/probe system. The specification explains that E9L was selected because it is an essential poxvirus gene and states that sequence changes within the targeted region are less likely to occur. The disclosure further explains that the particular probe has three base pair mismatches relative to the corresponding Variola sequence (¶[0040-0043]).
However, the claims are not limited to the disclosed embodiments. The claims also encompass detection of any “Mpox virus nucleic acid sequence” in combination with at least one second nucleic acid sequence that serves broadly as a positive or negative control. The claim therefore encompasses target/control combinations materially beyond the VAC1/E9L, RNase P, vaccinia, and other limited control embodiments actually described. The claimed scope therefore extends beyond the embodiments described in the specification.
State of the prior art and predictability of the art. At the time the application was filed, it was known how to perform real-time PCR detection of orthopoxvirus and Mpox virus nucleic acids, but the prior art demonstrated that the choice of the particular viral target determined what the assay could reliably identify. Li et. al. (Li Y, et. al. J Clin Virol. 2006 Jul;36(3):194-203. Epub 2006 May 30.) reported an E9L-NVAR assay that “detects Eurasian orthopoxviruses other than Variola” whereas a separate B6R assay “specifically detects monkeypox virus (MPXV).” Li validated the assays against panels of orthopoxvirus DNA and clinical lesion specimens rather than treating arbitrary portions of the Mpox genome as interchangeable diagnostic targets. The reference therefore evidences that selection of a nucleic acid target and corresponding primer/probe set materially affects the specificity and diagnostic function obtained.
The multiplex-PCR art likewise establishes that known PCR technology did not make arbitrary combinations of target and control assays predictably successful. Elnifro et. al. (Elnifro EM, et. al. Clin Microbiol Rev. 2000 Oct;13(4):559-70.) explains that “the optimization of multiplex PCRs can pose several difficulties, including poor sensitivity or specificity and/or preferential amplification of certain specific targets.“ The authors further explain that primer pairs that satisfy ordinary primer design parameters may nevertheless require empirical evaluation when combined, because primer/primer interactions, differential amplification efficiencies, annealing conditions, and competition among targets can alter assay performance. Elnifro further teaches that multiplex assays should be evaluated for sensitivity relative to the corresponding single-target assays before clinical application.
The prior art therefore shows a field in which the basic tools were mature, but the successful combination of particular viral targets, primers, probes, and controls remained context-dependent. This is consistent with the instant specification itself, which states that real-time PCR may be performed using “optimized cycling procedures depending on the primers and probes used”(¶[0042]). The specification’s successful use of the disclosed VAC1/E9L and RNAse P systems therefore would not reasonably establish that the broader target/control combinations encompassed by the claims could be practiced without further assay development and testing.
Level of skill in the art. One skilled in the art would have been familiar with nucleic acid extraction, primer and probe design, real-time PCR, multiplex PCR, Ct analysis, and the use of positive, negative, extraction, and specimen quality controls. The skilled artisan would have possessed the knowledge and algorithms to determine primers/probes for a specific known nucleic acid sequence. However, the existence of known methods for preparing and testing candidate embodiments does not establish that one skilled in the art would have known, without further experimentation, which additional Mpox virus nucleic acid sequences and targets would provide the claimed detection function and would satisfy the claimed limitations.
Working examples. The specification provides one working PCR example directed to a defined viral target/control assay; Example 1 identifies the non-variola Orthopoxvirus real-time PCR primers and probes and the RNase P primer and probes obtained from CDC, together with human genomic DNA and vaccina genomic material used in the assay control system (see Example 1 starting at ¶[0084]). Example 2 then describes MagNA Pure 96 nucleic acid extraction and purification, including lysis, binding of nucleic acids to magnetic glass particles, washing, and elution (¶[0085-0101]). Example 3 is the working PCR example (starting at ¶[0102]), where the specimen is tested using the E9L/VAC1 assay and RNase P, wherein RNAse P serves as the internal control, and the specification provides particular Ct criteria governing positive, negative, equivocal, and inconclusive results (¶[0102-0113]). The disclosure further describes re-extraction or re-amplification when specified controls fail. The example therefore demonstrates operation of a defined E9L/VAC1 and RNase P assay, not a representative range of materially different Mpox genomic targets paired with materially different positive or negative control sequences.
The specification does not provide working examples directed to multiplex real-time PCR using different portions of the Mpox genome with different primer/probe systems and different categories of control nucleic acids. Nor does it provide a series of working examples demonstrating that target/control combinations can be varied across the breadth of the claims while retaining acceptable specificity, sensitivity, and control performance. The disclosed examples therefore do not establish enablement across the full scope of the claims.
Guidance in the specification. The specification provides guidance regarding performing the embodiments actually selected by the inventors (see e.g. Examples 1-3 regarding VAC1/E9L/RNase P system for Mpox detection). However, the specification does not provide sufficient guidance regarding identifying other Mpox nucleic acid sequences that will provide the claimed diagnostic result. It does not provide a general sequence characteristic that identifies which portions of the Mpox genome should be selected, how the selected target should be distinguished from other related Orthopoxviruses, or which primer/probe combinations will retain adequate performance when multiplexed with an arbitrarily selected control assay. This omission is particularly material because ¶[0037] expressly recognizes that a sequence used as a monkeypox virus diagnostic need not itself be specific for monkeypox. The art, however, demonstrates that target selection affects whether an assay detects Mpox specifically or instead detects a broader class of orthopoxviruses.
The disclosure also fails to provide a general rule for selecting the second nucleic acid sequence of claim 1. The specification describes RNase P as a specimen and assay control, vaccinia genomic material as a positive amplification control, and extraction control carried through sample processing, and additional human-gene controls (¶[0040-0041][0060]). These embodiments illustrate several different control functions, but do not establish that a substantially unrestricted nucleic acid sequence capable of being characterized as a positive or negative control can simply be substituted into the claimed multiplex assay while preserving reliable detection of the viral target.
Quantity of experimentation necessary. To practice the full scope of the claims, one skilled in the art would need to identify additional Mpox genomic regions for detection, select or design corresponding primers and probes, and determine whether the resulting assay provides an appropriate diagnostic signal. The artisan would then have to select a second nucleic acid control suitable for the desired control function and determine whether that assay operates compatibly with the selected viral assay under common multiplex conditions. Candidate combinations would require empirical evaluation for such matters as amplification efficiency, cross-reactivity, interference between primer/probe systems, appropriate Ct behavior, and whether both the viral target and control continue to perform their intended functions int eh combined assay.
Such experimentation would not merely involve the routine application of known methods to embodiments reasonably expected to work. Instead, one skilled in the art would need to prepare and test additional primer/probe embodiments to determine whether they satisfy the claimed detection function. Although the individual methods used to prepare and test candidate embodiments may have been known in the art, the relevant inquiry is not whether one skilled in the art could perform the required assays. The relevant inquiry is whether the specification provides sufficient guidance to identify and practice the embodiments falling within the full scope of the claims without undue experimentation. Here, one skilled in the art would need to prepare and test additional target and control assay combinations to determine which embodiments satisfy the ability to detect and diagnose Mpox virus infection.
Amgen. The Supreme Court has explained that a specification need not describe with particularity how to make and use every embodiment within a claimed class. However, the disclosure must enable one skilled in the art to make and use the full scope of the claimed invention. A reasonable amount of experimentation may be permissible depending on the nature of the invention and the underlying art. Amgen Inc. v. Sanofi, 598 U.S. 594, 610-13 (2023).
In the instantly claimed invention, the specification describes the VAC1/E9L assay, the identified RNase P primer/probe control, vaccinia and other specified controls, and concrete extraction and purification procedures, but the claims also encompass materially different Mpox target sequences and target/control multiplex combinations. The specification does not identify a general quality or provide sufficient guidance that would allow one skilled in the art to practice that broader scope without undue experimentation.
Conclusion. For the reasons discussed above, the specification does not enable one skilled in the art to make and/or use the full scope of the invention recited in the claims without undue experimentation.
Claim Rejections - 35 USC § 102
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
(Rejection withdrawn.) The rejection of Claims 1-7, 11-17, and 19 under 35 U.S.C. 102(a)(1) as being anticipated by Quest Diagnostics (Quest Diagnostics. Quest Diagnostics Monkeypox Virus Qualitative Real-Time PCR Emergency Use Authorization (EUA) Summary. Ver. September 15, 2022. Earlier version of EUA accessed via WayBack Machine https://www.fda.gov/media/161457/download.; hereafter “Quest Diagnostics”) is withdrawn in light of the amendments to the claims.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
(Rejection withdrawn.) The rejection of Claims 8-10, 18, and 20 under 35 U.S.C. 103 as being unpatentable over Quest Diagnostics as applied to claims 1-7, 11-17, and 19 above, and further in view of Springer et. al. (US20230248338A1; Priority 08/30/2020; hereafter “Springer”), LabCorp (LabCorp. SPECIMEN COLLECTION GUIDE: Mpox (Orthopoxvirus), DNA, PCR Collection Instructions. 08/31/2022. https://www.labcorp.com/assets-media/2734; hereafter “LabCorp”), and Commonwealth of Virginia (“Monkey pox Testing Instructions FAQ.” Commonwealth of Virginia, Dept. of General Services, Richmond, VA. Rev. 2, Pub. 08/01/2022. https://www.vdh.virginia.gov/content/uploads/sites/13/2022/08/Monkey-pox-Testing-Instructions-FAQ.pdf.; hereafter “Commonwealth of Virginia”) as evidenced by LabCorp (LabCorp. Mpox/Orthopoxvirus (Formerly Monkeypox) for Providers. https://www.labcorp.com/infectious-disease/mpox (Wayback Machine earliest capture 18 Dec 2022.; hereafter “LabCorp-2022a”) and CDC (Centers for Disease Control and Prevention (CDC). "Labcorp to begin monkeypox testing today, doubling nationwide testing capacity." 07/06/2022. https://archive.cdc.gov/#/details?url=https://www.cdc.gov/media/releases/2022/s0706-monkeypox-labcorp.html. ; hereafter “CDC”) is withdrawn in light of the amendments to the claims.
(Rejection withdrawn.) Claims 1, 3, 5, 9-14, and 17-19 are rejected under 35 U.S.C. 103 as being unpatentable over Quest Diagnostics (Quest Diagnostics. Quest Diagnostics Monkeypox Virus Qualitative Real-Time PCR Emergency Use Authorization (EUA) Summary. Ver. September 15, 2022. Earlier version of EUA accessed via WayBack Machine https://www.fda.gov/media/161457/download.; CITED ART OF RECORD; hereafter “Quest Diagnostics”)
in view of Springer et. al. (US20230248338A1; Priority 08/30/2020; CITED ART OF RECORD; hereafter “Springer”), Butts et. al. (US20170232437A1, Pub. 08/17/2017; hereafter “Butts”), and
in further view of LabCorp (LabCorp. SPECIMEN COLLECTION GUIDE: Mpox (Orthopoxvirus), DNA, PCR Collection Instructions. 08/31/2022. https://www.labcorp.com/assets-media/2734; CITED ART OF RECORD; hereafter “LabCorp”), and Commonwealth of Virginia (“Monkey pox Testing Instructions FAQ.” Commonwealth of Virginia, Dept. of General Services, Richmond, VA. Rev. 2, Pub. 08/01/2022. https://www.vdh.virginia.gov/content/uploads/sites/13/2022/08/Monkey-pox-Testing-Instructions-FAQ.pdf.; CITED ART OF RECORD; hereafter “Commonwealth of Virginia”) as evidenced by LabCorp (LabCorp. Mpox/Orthopoxvirus (Formerly Monkeypox) for Providers. https://www.labcorp.com/infectious-disease/mpox (Wayback Machine earliest capture 18 Dec 2022.; CITED ART OF RECORD; hereafter “LabCorp-2022a”) and CDC (Centers for Disease Control and Prevention (CDC). "Labcorp to begin monkeypox testing today, doubling nationwide testing capacity." 07/06/2022. https://archive.cdc.gov/#/details?url=https://www.cdc.gov/media/releases/2022/s0706-monkeypox-labcorp.html. ; CITED ART OF RECORD; hereafter “CDC”.)
The Prior Art
Quest Diagnostics teaches a monkeypox virus qualitative real-time PCR assay (entire document; see EUA abstract.) Quest Diagnostics teaches qualitative detection of DNA from monkeypox virus (West African clade; clade II) and non-variola Orthopoxvirus in lesion swab specimens (i.e., swabs of acute pustular or vesicular rash) in universal viral transport media (UTM) from individuals suspected of monkeypox virus infection by their healthcare provider (p. 1, “Intended Use”). Quest Diagnostics teaches the multiplexed targets detected are RNaseP as the internal endogenous control, E9L, TNF, and an internal processing control (IPC) (pp. 2-3, “Device Description and Test Principle: Quest Diagnostics Monkeypox Virus Qualitative Real-Time PCR”; instant claims 3, 5, 14.) Quest Diagnostics teaches the viral nucleic acid is isolated from a swab of the lesion, wherein the isolation comprises a 96-well extraction system (p. 2, “Device Description and Test Principle: Quest Diagnostics Monkeypox Virus Qualitative Real-Time PCR”; instant claims 12-13.) Quest Diagnostics teaches the use of the MAGNA PURE® system, which inherently comprises the use of magnetic glass particles for binding the nucleic acid within the sample (p. 2, “Device Description and Test Principle: Quest Diagnostics Monkeypox Virus Qualitative Real-Time PCR”; instant claim 11.) The instrumentation for performing the real-time PCR (ABI 7500 Real-Time PCR or ABI 7500 Fast Real-Time PCR instruments) comprises the use of a computer interface (p. 2, “Device Description and Test Principle: Quest Diagnostics Monkeypox Virus Qualitative Real-Time PCR”; instant claim 19.)
While Quest Diagnostics teaches the majority of the instant claims, Quest Diagnostics has stated that their methods have not been tested on dry swabs, only swabs that have been provided/collected in transport media. Additionally, the instructions from Quest Diagnostics are for a medical professional and do not appear to suggest or teach self-collection by a non-medical professional, or kits that allow for self-collection of samples by the subject who is experiencing symptoms. However, such limitations were known in the prior art for various reasons, as evidenced by the teachings of Springer, Butts, and Commonwealth of Virginia.
Commonwealth of Virginia provides a frequently asked question (FAQ) for monkeypox testing (entire document), and teaches that for each test, 2 swabs should be collected per lesion, and all lesions should be swabbed if they are in different body parts/areas (p. 1, “DCLS Testing”). Commonwealth of Virginia teaches that one should not use cotton swabs, as they interfere with PCR test methods, and swabs that are used should be nylon, polyester, or Dacron with plastic, wood, or aluminum shafts (p. 1, “DCLS Testing.”; instant claim 9) Commonwealth of Virginia teaches that no viral or universal transport media should be used, and the swabs should be dry and left dry in separate dry, sterile tubes (Table, p. 1; p. 3, Item 6). Note that Commonwealth of Virginia has shown that, via the CDC website, that LabCorp has initiated Monkeypox testing (https://www.cdc.gov/media/releases/2022/s0706-monkeypox-labcorp.html, which links to https://archive.cdc.gov/#/details?url=https://www.cdc.gov/media/releases/2022/s0706-monkeypox-labcorp.html, which further links to https://www.labcorp.com/infectious-disease/mpox).
LabCorp teaches for monkeypox (Mpox) collection, two swabs are provided, along with universal transport medium (UTM) or viral transport medium (VTM) and must be used for the collection of mpox (Orthopoxvirus), DNA, PCR (“Collection Information”.) LabCorp teaches the swabs may be made of polyester, rayon or Dacron (“Collection Information: Please note.”) After collection, the specimens must be placed in a biohazard bag (“Sample Submission.”)
Springer teaches swabs that are automation compatible and kits and methods of use for said swabs (entire document; see abstract; ¶[0006].) Springer teaches the swabs are compatible with dry or wet transport and self-swabbing at home (¶[0221][0224][0237][0239]; instant claims 10, 18). Springer teaches the swabs would be made of material compatible for RT-PCR testing, especially automated testing, yet are comfortable for patients to self-administer at home (¶[0239]). Springer teaches kits which comprise the swabs useful for self-collection, which comprise the swab, transport container, instructions for use, and packaging for maintaining the temperature during transport (reference claim 46; ¶[0152-160]). Springer does not merely suggest that cellular nucleic acid can be recovered from a swab; instead, Springer expressly evaluates the “elution of viral particles” from swabs and teaches that packaged viral particles dried onto a swab were released into the PBS by agitation and subsequently detected by PCR. Springer reports that the swabs released viral material into solution and further concludes that the disclosed swabs permit rapid accessioning and processing of viral specimens (¶[0244-0248][0252]).
Butts further teaches that multi-well processing of swabs was already known in the art, as Butts further explains that laboratories processing large numbers of samples used 24-, 96-, or 384-well formats, with 96-well formats being the most common, and specifically identifies the Promega SlicPrep 96 device as a known device that permits swabs to be raised and lowered into the processing buffer. Butts further teaches positioning swab-containing extraction components over a 96-well deep well plate, lowering the swabs into liquid, transferring biological material from the swabs into the liquid, and thereafter processing the resulting material using liquid handlers or magnetic processors (¶[0003-0008][0016-0020]).
Given the teachings of Quest Diagnostics, Springer, LabCorp, Butts, and Commonwealth of Virginia, one would be apprised as to kits designed for collecting samples from suspected Mpox lesions, especially the use of non-cotton swabs for said collection, and to utilize high-throughput swab processing techniques taught by Springer in the known multi-well swab processing format taught by Butts. Given the teachings of Springer, one of skill in the art would be apprised as to the usefulness of having said kits be ready for home or self-collection, and the various components which would be in said kit. Given the teachings of Commonwealth of Virginia and Springer, one of skill in the art would be apprised that swab collection could be done with or without transport media, and in the case of Commonwealth of Virginia, said Mpox swabs were absolutely not to be submitted in any type of transport media. Given the teachings of LabCorp, it would be obvious to a skilled artisan that the swab samples should be collected in biohazard bags. Given the combined teachings of Quest Diagnostics, Springer, LabCorp, Butts, and Commonwealth of Virginia, arriving at the limitations of instant claims 1 and 17 and further instant dependent claims 3, 5, 9-14, and 18-19 would be obvious to a skilled artisan.
It would have been obvious to one of ordinary skill in the art to modify the methods and compositions taught by Quest Diagnostics in order to take dry swab samples and/or have home collection kits. One would have been motivated to do so, given the suggestion by Springer that swabs could be designed for easier home collection, and could then be processed in an automated format. There would have been a reasonable expectation of success, given the knowledge that kits with specific collection components were suggested in the art, as taught by Springer, LabCorp, Butts, and Commonwealth of Virginia. There would have been further reasonable expectation of success, as automated swab processing units for 96-well plate formats were known in the art, as taught by Butts. Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Response to Arguments
Applicant’s arguments, see “Remarks”, filed 07/01/2026, with respect to the rejections of the claims under Quest Diagnostics have been fully considered and are persuasive, as Quest Diagnostics fails to teach the use of a swab for isolation of the sample. Therefore, the rejection has been withdrawn. However, upon further consideration, new grounds of rejection are made in view of Springer, LabCorp, Commonwealth of Virginia, and Butts.
Applicant argues that the cited art fails to teach the asserted point of novelty of eluting a dry swab directly into a 96-well plate format. However, this argument is not commensurate in scope with the instant claims, as the feature which the applicant relies upon is not recited in the instantly rejected claims. If this is the actual point of novelty of the instant invention, it is highly suggested that such a limitation specifically be incorporated into the claims. Although the claims are interpreted in light of the specification, limitations from a disclosed embodiment are not read into the claims (MPEP §2145.VI.).
Applicant argues that the teachings of Springer, LabCorp, Commonwealth of Virginia, LabCorp-2022a, and CDC fail to cure the deficiencies of Quest Diagnostics. The Office fails to find this argument persuasive. Quest Diagnostics is relied upon to teach the Mpox lesion-swab diagnostic method, viral nucleic acid purification, and multiplex real-time PCR detection, while the additional references are relied upon for the swab type/processing and multiwell extraction features not expressly disclosed by Quest Diagnostics. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Applicant’s general allegation that the additional references fail to cure the deficiencies of Quest Diagnostics is not persuasive because it does not address the combined teachings of the applied references or establish that one of ordinary skill would have lacked reason or a reasonable expectation of success in making the proposed combination.
For at least these reasons, Applicant’s arguments are not persuasive, and the claims stand rejected as being obvious in view of the prior art.
Double Patenting
The text regarding nonstatutory double patenting was presented in a previous Office action.
(Rejection withdrawn.) The provisional rejection of Claims 1-20 on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 18/500,064 (reference application) in view of Quest Diagnostics (supra) is withdrawn in light of the amendments to the claims.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
US20120208179A1. Teaches PCR-based identification of orthopoxviruses using targets such as E9L and teaches using swabs from DNeasy96 tissue kit. Not utilized as rejection would be redundant to those set forth supra.
US20240218467A1. Post-filing art which teaches MPOX nucleic-acid detection and established Orthopoxvirus E9L assays.
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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/RACHEL B GILL/
Primary Examiner, Art Unit 1671
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