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 .
Status of the Claims
Claims 14, 17-23, 26-27, 29-30, and 34-37 are pending in the application and are the subject of this office action.
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 26-27, 29-30, 34-37 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 an embodiment wherein the anti MHCI allele antibody is specific for a different chain (i.e. alpha or beta) of the MHCI molecule than the chain to which the first label is attached, does not reasonably provide enablement for the full scope of the claim, wherein the anti-MHCI allele antibody may bind specifically to the same chain of the MHCI molecule as the first label. 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 or use the invention commensurate in scope with these claims.
A determination of enablement involves the consideration of the following factors: the breadth of the claims; the nature of the invention; the state of the prior art; level of one of ordinary skill; level of predictability in the art; amount of direction provided by the inventor; existence of working examples; and quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Claim 26 recites a labeled MHCI molecule comprising a first label, an alpha chain, and a beta chain (wherein the first label is therefore presumably attached to either the alpha chain or the beta chain of the MHCI molecule). The claim further recites contacting the labeled MHCI/ligand peptide complex with an antibody complex comprising an anti-MHCI allele antibody covalently attached to a FRET acceptor and a FRET emitter complex comprising a FRET emitter conjugated to a second label, wherein the second label specifically binds to the first label of the MHCI/-second peptide complex. The claim further recites detecting FRET emission of the FRET emitter conjugated to the second label in the reaction composition, thereby detecting binding of a MHCI allele to a peptide as a measure of the level of peptide exchange.
One of ordinary skill in the art will recognize that if FRET emission is to be used to indicate the level of peptide exchange (i.e. binding of the MHCI molecule to a test peptide), then there must be some mechanism by which the proximity of the FRET emitter and the FRET acceptor is changed in accordance with the level of peptide exchange, such that a change in FRET emission could be observed.
The instant specification provides limited direction and no exact reduction to practice for this assay. One working example of a very similar FRET assay is discussed in the specification, as shown in Fig. 8A and discussed in associated example 3, starting at Par. 203. In this example, the MHCI/peptide complex comprises a first label which is specifically biotin and which is specifically attached to the alpha chain of the MHCI molecule. The composition further comprises a second label which is specifically streptavidin conjugated to a FRET acceptor (APC). As such, the streptavidin second label specifically binds to the biotin first label (attached to the MHCI alpha chain), such that the FRET acceptor is held in proximity to the MHCI alpha chain. An antibody complex comprising an anti-MHCI allele antibody which is specifically an anti-B2M antibody and a FRET emitter, specifically binds to the beta chain of the MHCI molecule. As such, in an embodiment wherein the test peptide does not bind to the MHCI molecule, the MHCI molecule is destabilized by loss of the original UV cleavable ligand peptide, and the alpha chain and the beta chain of the MHCI molecule dissociate from one another, such that the FRET emitter and FRET acceptor are not held in proximity to one another; in an embodiment wherein the test peptide does bind to the MHCI molecule, the MHCI molecule is stabilized by binding to the test peptide, such that the alpha and beta chains of the MHCI molecule remain in complex with one another, and the FRET emitter and FRET acceptor are held in proximity to one another. This therefore enables a change in FRET signal which can be used as a measure of the level of peptide exchange, as recited in step (d) of claim 26. This reduction to practice differs slightly from the instant claim because the instant claim indicates that the anti-MHCI antibody is conjugate to a FRET acceptor, while the second label is conjugated to a FRET emitter; in contract, Fig. 8A (and associated example 3) show an anti-MHCI antibody conjugated to a FRET emitter and a second label conjugated to a FRET acceptor.
However, this reduction to practice does not enable the full scope of the instant claim, as the instant claim does not specify that the first label and the anti-MHCI allele antibody must specifically bind to different chains of the MCHI molecule. Therefore, the claims encompass embodiments wherein both the first label and the anti-MHCI allele antibody bind to the alpha chain, and embodiments wherein both the first label and the anti-MHCI allele antibody bind to the beta chain. In these embodiments, detection of FRET emission cannot be used to detect binding of a MHCI allele to a peptide as a measure of the level of peptide exchange because there would be no observable change in FRET emission based on the level of peptide exchange. That is, if both the first label and the antibody bind to the same chain of the MHCI molecule, the FRET emitter and the FRET acceptor would be expected to remain in proximity to one another regardless of whether the MHCI molecule binds to the peptide and regardless of whether the alpha and beta chains of the MHCI molecule remain in complex or dissociate from one another. Therefore, there would be no detectable change in FRET emission which could be correlated with the level of peptide exchange as required by the instant claim.
Dependent claims 27, 29-30, 34-37 provide further limitations on the FRET assay but do not resolve this issue. Notably, claim 30 indicates that the antibody is specifically anti-HLA, but this still does not enable the full scope of the claim because the claims do not specify whether the first label is attached to the alpha chain or the beta chain of the MHCI molecule.
As such the quantity of experimentation needed to enable the full scope of the claims is undue because the claims encompass embodiments which do not appear to be capable of fulfilling the functional limitations of the claims.
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 19, 22, 26-27, 29-30, and 34-37 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 19 is vague regarding “the free second peptide”. There is no prior introduction of a “free second peptide” in claim 19 or in the claims from which it depends, therefore there is insufficient antecedent basis for this limitation in the claim.
Claims 22 and 26 are rejected as indefinite over recitation of “each peptide” (claim 22) and “a peptide” (claim 26). There is introduction of multiple different peptides within the preceding claims, such that it is unclear exactly which peptide is being reference by generic recitation of “peptide”. Clarification is required.
Claim 22 is rejected as indefinite because the chronology of the additional limitation within the method of the independent claim is unclear. That is, it is not clear whether the test peptides are identified before or after peptide exchange.
Claim 26 is vague regarding “the labeled MHCI/ligand peptide complex”. There is no prior introduction of a “labeled MHCI/ligand peptide complex” therefore there is insufficient antecedent basis for this limitation in the claim. Additionally, recitation of “the labeled MHCI/ligand peptide complex” in step (d) of the claim is confusing because the term appears to refer to the ligand peptide introduced in step (a)(ii) and therefore to the complex of MHCI and the ligand which comprises a UV-cleavable amino acid, but this complex is cleaved by exposure to UV light in preceding steps (b)-(c) of the claim.
Dependent claims 27, 29-30, and 34-37 are rejected as indefinite because they depend from an indefinite claim and fail to remedy its deficiencies.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 14, 17-21, and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Hadrup et al ((2009) "High-throughput T-cell Epitope Discovery Through Mhc Peptide Exchange", Methods in Molecular Biology, 524:383-405.; IDS entered) in view of Stoll et al (Two-dimension liquid chromatography: a state of the art tutorial. Analytical Chemistry 2017 89 (1), 519-531; previously cited).
Regarding claims 14, 17-18, and 20, Hadrup teaches a peptide exchange assay for determining binding of a MHCI allele to a test peptide (Abstract), comprising:
Providing a first composition comprising a test peptide and a MHCI/ligand complex comprising a MHCI molecule comprising an alpha chain, a beta chain, and a ligand, wherein the ligand is a peptide comprising a non-natural UV-cleavable amino acid (Fig. 2, MHC ligand discovery; Section 3.1.2; Section 3.2, Section 3.2.1 step 6: MHCI complex comprising MHC heavy chain (alpha chain) and B2M (beta chain) and a conditional ligand (a peptide comprising a non-natural UV-cleavable amino acid); Section 3.3.);
Exposing the first composition to UV light to cleave the ligand at the UV-cleavable amino acid (Section 3.3, Par. 1, and step 2: UV-mediated cleavage of the conditional ligand);
Incubating the first composition for a period of time to form a second composition comprising free test peptide, the alpha chain, the beta chain, and/or a MHCI/-second peptide complex (Section 3.3, steps 1-3);
Determining whether the MCHI allele is bound to the second peptide (Section 3.4: measuring peptide mediated MHC rescue by MHC ELISA; Section 3.4.3: analysis of peptide exchange reactions by gel filtration chromatography; Fig. 2).
Hadrup further teaches performing HPLC or MS to distinguish the MHCI and the second peptide; wherein the presence of the second peptide as determined by HPLC and MS indicates that the MHCI is capable of binding to the second peptide (Pg. 403, note 17: pMHC complexes can be analyzed by HPLC or MS; Section 3.4.3; Fig. 5).
Hadrup does not explicitly teach performing HPLC and MS to distinguish the MHCI and the second peptide.
However, It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the invention of Hadrup to specifically comprise performing both HPLC and MS. One of ordinary skill in the art would be motivated to make this modification because redundancy of analysis by different methods confirms and improves accuracy of results, and Hadrup teaches that both HPLC and MS are valuable as independent methods for confirmation and analysis of peptide exchange (Pg. 403, note 17). One of ordinary skill in the art would have a reasonable expectation of success in making this modification because Hadrup teaches that HPLC and MS are appropriate for this application.
Hadrup differs from the instant claims in that it does not explicitly teach 2D LC/MS.
Regarding 2D LC/MS, Stoll teaches that 1D LC is often unable to quickly separate mixtures of interest in two particular situations: (a) mixtures that are too complex in a general sense, and thus outstrip the ability of 1D LC to entirely separate the mixture into distinct components and (b) mixtures that are not necessarily complex per se, but contain several species of interest that are very difficult to resolve, either because there are just too many compounds to avoid overlap or due to the presence of closely related compounds (Pg. 519, Col. 2, Par. 1). Stoll teaches that 2D/LC is advantageous in separating and analyzing different analytes in a mixture based on two different dimensions of LC, and that 2D/LC is especially useful in peptide fingerprinting and identification in combination with MS (Pg. 519, Col. 2, Par. 1; Pg. 521, Col. 1, Par. 3; Pg. 527, Col. 1, Par. 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the invention of Hadrup to further include wherein the level of MHCI/second peptide complex is measured by 2D LC/MS wherein 2D LC/MS comprises removing the free second peptide from the second composition. One would be motivated to make this modification because Stoll teaches that 2D LC is advantageous over 1D LC and is particularly useful and effective in separating and analyzing different components of mixtures comprising different species of interest, and teaches specifically that 2D LC can be used in combination with MS for peptide fingerprinting and identification. One of ordinary skill in the art would have a reasonable expectation of success in making this modification because Hadrup teaches that both LC and MS may be used for separation and analysis of components in the assay mixture.
Regarding claim 19, Hadrup further teaches the assay wherein the free second peptide is removed from the second composition via size exclusion chromatography (Fig. 5; Section 3.4.3: gel filtration chromatography; Section 3.3: resulting complexes may be used to determine exchange efficiency by gel filtration chromatography).
Regarding claim 21, Hadrup further teaches the assay wherein a plurality of the MHCI/ligand complex is combined with at least two different test peptides (Pg. 403, step 17: parallel exchange reactions involving high numbers of peptides; Fig. 2: peptide library of potential MHC ligands; Abstract).
Regarding claim 23, Hadrup further teaches the assay wherein the test peptide is present in the first composition at a ratio of at least 10:1 (test peptide:MHCI) (Section 3.3: in routine experiment a 100 fold molar excess of peptide over MHC is used).
Claims 14, 17-21, and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Toebes et al ((2006) "Design and Use of Conditional MHC Class I Ligands", Nature Medicine, 12(2):246-251.; IDS entered) in view of Stoll et al (Two-dimension liquid chromatography: a state of the art tutorial. Analytical Chemistry 2017 89 (1), 519-531; previously cited).
Regarding claims 14, 17-18 and 20, Toebes teaches a peptide exchange assay for determining binding of a MHCI allele to one or more test peptide (Abstract), comprising:
Providing a first composition comprising one or more test peptide and a MHCI/ligand complex comprising a MHCI molecule comprising an alpha chain, a beta chain, and a ligand, wherein the ligand is a peptide comprising a non-natural UV-cleavable amino acid (Pg. 250, Col. 1, Par. 4: Peptide synthesis and preparation of recombinant MHC);
Exposing the first composition to UV light to cleave the ligand at the UV-cleavable amino acid (Pg. 250, Col. 1, last Par.-Col. 2, first Par.);
Incubating the first composition for a period of time to form a second composition comprising free test peptide, the alpha chain, the beta chain, and/or a MHCI/-second peptide complex (Pg. 250, Col. 1, last Par.-Col. 2, first Par.);
Determining whether the MCHI allele is bound to the second peptide, wherein MHCI allele binding to the one or more test peptide is determined by measuring the level and distinguishing the identity of the MHCI/second peptide complexes in the second composition, and wherein the level of MHCI/second peptide complex is measured and its identity is distinguished by LC and MS comprising HPLC (Fig. 2; Pg. 247, Col. 1, Par. 1-Col. 2, Par. 2).
Toebes teaches LC and MS analysis for analyzing and determining levels of MHCI/second peptide complex, but differs from the instant claims in that it does not specifically teach 2D LC/MS.
Regarding 2D LC/MS, Stoll teaches that 1D LC is often unable to quickly separate mixtures of interest in two particular situations: (a) mixtures that are too complex in a general sense, and thus outstrip the ability of 1D LC to entirely separate the mixture into distinct components and (b) mixtures that are not necessarily complex per se, but contain several species of interest that are very difficult to resolve, either because there are just too many compounds to avoid overlap or due to the presence of closely related compounds (Pg. 519, Col. 2, Par. 1). Stoll teaches that 2D/LC is advantageous in separating and analyzing different analytes in a mixture based on two different dimensions of LC, and that 2D/LC is especially useful in peptide fingerprinting and identification in combination with MS (Pg. 519, Col. 2, Par. 1; Pg. 521, Col. 1, Par. 3; Pg. 527, Col. 1, Par. 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the invention of Toebes to further include wherein the level of MHCI/second peptide complex is measured by 2D LC/MS wherein 2D LC/MS comprises removing the free second peptide from the second composition. One would be motivated to make this modification because Stoll teaches that 2D LC is advantageous over 1D LC and is particularly useful and effective in separating and analyzing different components of mixtures comprising different species of interest, and teaches specifically that 2D LC can be used in combination with MS for peptide fingerprinting and identification. One of ordinary skill in the art would have a reasonable expectation of success in making this modification because Toebes teaches that both LC and MS may be used for separation and analysis of components in the assay mixture.
Regarding claim 19, Toebes further teaches the assay wherein the free second peptide is removed from the second composition via size exclusion chromatography (Fig. 2; Pg. 247, Col. 1, Par. 1-Col. 2, Par. 2; gel filtration chromatography).
Regarding claim 21, Toebes further teaches the assay wherein a plurality of the MHCI/ligand complex is combined with at least two different test peptides (Pg. 249, Col. 1, last Par.-Col. 2, first Par.; Pg. 250, Col. 1, last Par.-Col. 2, Par. 2).
Regarding claim 23, Toebes further teaches the assay wherein the test peptide is present in the first composition at a ratio of at least 10:1 (test peptide:MHCI) (Pg. 450, Col. 1, last Par.-Col. 2, Par. 2: MHCI present at 0.5uM, test peptide present at 50uM).
Claim 22 is rejected under 35 U.S.C. 103 as being unpatentable over Hadrup et al ((2009) "High-throughput T-cell Epitope Discovery Through Mhc Peptide Exchange", Methods in Molecular Biology, 524:383-405.; IDS entered) in view of Stoll et al (Two-dimension liquid chromatography: a state of the art tutorial. Analytical Chemistry 2017 89 (1), 519-531; previously cited) as applied to claim 21 above, and further in view of Toebes et al ((2006) "Design and Use of Conditional MHC Class I Ligands", Nature Medicine, 12(2):246-251.; IDS entered).
Regarding claim 22, Hadrup teaches the method of claim 21, as described above. Hadrup further teaches that MS can be used for the analysis of parallel exchange reactions involving high numbers of peptides, and teaches that these techniques are valuable to follow the peptide exchange process by an independent method. Hadrup differs from the instant claim in that it does not explicitly teach that the test peptides are identified by MS based on the predicted mass of each peptide.
Toebes further teaches that MS can be used to verify the identity of the peptide bound to the MHCI complex after performance of the exchange assay, wherein verification is based on the expected mass of the test peptide (Pg. 247, Col. 2, last Par.-Pg. 248, Col. 1, first Par.: upon UV-light mediated cleavage, the sole detectable peptide mass associated with HLA-A2.1 corresponds to the mass of the CMV pp65(495-503) epitope).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the invention of Hadrup to further comprise identification of the multiple different test peptides by mass spectrometry based on the predicted mass of each test peptide, as taught by Toebes. One of ordinary skill in the art would be motivated to make this modification because the implementation of MS in this fashion allows the practitioner of the assay to verify the identity of the test peptide bound to the MHC complex, as taught by Toebes. One of ordinary skill in the art would have a reasonable expectation of success in making this modification because MS is a technique that is known and commonly used in the art to distinguish and identify proteins and peptides based on their mass, and because both Toebes and Hadrup are directed to peptide exchange assays used to screen pluralities of test peptides for their ability to bind to an MHCI complex.
Subject Matter Free of Prior Art
Claims 26-27, 29-30, and 34-37 are rejected as described above, but appear to be free of the prior art.
Regarding claims 26-27, 29-30, and 34-37, the closest prior art is Hadrup et al ((2009) "High-throughput T-cell Epitope Discovery Through Mhc Peptide Exchange", Methods in Molecular Biology, 524:383-405.; IDS entered) and Toebes et al ((2006) "Design and Use of Conditional MHC Class I Ligands", Nature Medicine, 12(2):246-251.; previously cited), as described in the 103 rejections above. Additional prior art of interest is Axmann et al ("Measuring TCR-pMHC Binding In Situ using a FRET-based Microscopy Assay," Journal of Visualized Experiments, 104:e53157 (2015) 17 pgs.; IDS entered), Weissbrich et al (US 2018/0042995 A1; previously cited), and Rooney et al (WO 2020/132586 A1; IDS entered).
Hadrup further teaches an ELISA assay for detection of the binding of a MHCI allele to a peptide. The ELISA comprises detection of a biotinylated pMHC complex by capture of the biotinylated complex on a streptavidin coated plate and an antibody complex compriaing an anti-MHCI allele antibody labeled with HRP (Fig. 4). This is similar to instant claim 26 in that the assay comprises a labeled anti-MHCI allele antibody and a labeled (biotinylated) pMHC complex which binds to a second label (streptavidin).
Both Hadrup and Toebes differ from instant claim 26 in that they do not teach a FRET assay.
Regarding claim 26, Axmann and Weissbrich both teach assay comprising the use of FRET to detech binding of a T cell receptor to a pMHC complex (see Weissbrich, Fig. 12; see Axmann, Fig. 2; both references show a T cell or TCR labeled with either a FRET donor or acceptor, and an immobilized pMHC complex labeled with either a FRET donor or acceptor, such that the FRET labels are brought into proximity and produce detectable signal when the TCR binds to the immobilized pMHC).
Both Axmann and Weissbrich differ from the instant claim in that the FRET assay is used to detect binding of the TCR to the pMHC complex, rather than to detect binding of a peptide to an MHCI complex. Additionally, neither Axmann nor Weissbrich teaches an antibody complex comprising an anti-MHCI allele antibody covalently attached to a FRET acceptor or a FRET emitter conjugated to a second label.
Regarding claim 26, Rooney teaches an MHCII peptide exchange assay wherein peptide exchange is detected by TR-FRET (Par. 174, 345, 716, 721-722, Fig. 26A). However, the FRET assay taught by Rooney differs from the instant claim in function and basic structure. The assay taught by Rooney comprises a first antibody conjugated to a first FRET label, wherein the antibody specifically binds to the placeholder peptide (i.e. the peptide that is replaced during the peptide exchange assay); a second FRET label is conjugated to a second antibody which is an anti-his antibody. As such, the Rooney’s assay comprises two antibodies which are brought into proximity by binding to both the placeholder peptide and the MHCII prior to peptide exchange, wherein proximity of the two FRET labels produces a detectable fluorescent signal. When peptide exchange successfully occurs, the placeholder peptide is displaced by the test peptide, such that the placeholder peptide and the first antibody and first FRET label dissociate from the MHC complex while the second anti-his antibody and the second FRET label remain bound to the MHC complex; this increases the distance between the two FRET labels, and as such, successful peptide exchange results in a decrease in fluorescent signal. This differs from the assay of claim 26 where increased FRET emission in the reaction composition indicates binding of the MHCI to the test peptide.
Rooney further differs from the instant claim in that it is directed to peptide exchange with MHCII rather than MHCI.
Response to Arguments
Applicant’s arguments filed 15 July 2026 have been fully considered.
Objections to the Drawings and Specification are withdrawn in view of the amendments.
Previous grounds of 112(a) rejection are withdrawn and new grounds of 112(a) rejection which address the amended claims are presented above.
Regarding the 112(b) rejections, Applicant argues that one of ordinary skill in the art would recognize that the second peptide represents the specific second peptide that is bound by the MHCI allele, which can be, but is not necessarily, the test peptide. Applicant argues that it is the objective of the method to determine whether the second peptide is indeed to the test peptide (or a specific test peptide when more than one test peptide is employed). This argument is persuasive in view of the amendments to the claims, and the 112(b) rejections over this term are withdrawn. However, it is noted that the 112(b) rejection of claim 19 over recitation of the “free second peptide” is maintained; wherein claim 14 from which claim 19 depends recites “free test peptide” but the only introduction of a second peptide in claim 19 is in the context of the recited MHCI complex, such that there is no introduction of any “free second peptide” in the claimed assay, and there is insufficient antecedent basis for this limitation in the claim.
Regarding other 112(b) rejection, Applicant argues generally that these are overcome by the amendments to the claims. The 112(b) rejections are withdrawn except where restated above, and new grounds of 112(b) rejection which address the amended claims are presented above.
The previous 102 and 103 rejections are withdrawn in view of the amendments to the claims, and new grounds of 103 rejection which address the amended claims are presented above.
Applicant argues that the combination of Hadrup or alternatively Toebes with Stoll to teach 2D LC/MS lacks the requisite motivation, indicating note 17 of Hadrup which indicates drawbacks to the use of mass spectrometry based approaches.
This argument is not persuasive for the combination of Toebes and Stoll because Applicant has not provided specific argument to address this combination and to overcome the motivation to combine Toebes and Stoll in particular, and Toebes explicitly teaches the use of HPLC and MS in the disclosed assay.
This arguments is also not persuasive for the combination of Hadrup and Stoll, because when read in full, note 17 of Hadrup explicitly states that MS and HPLC techniques “may be valuable to follow the peptide exchange process by an independent method” indicating that there is motivation to perform these methods explicitly given within the reference even if they are understood to have some drawbacks.
Conclusion
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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/ELLIS FOLLETT LUSI/Examiner, Art Unit 1677
/CHRISTOPHER L CHIN/Primary Examiner, Art Unit 1677
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