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 10 Oct 2025 is acknowledged. Claims 15-22, 24-25 and 29 are currently pending. Of those, claim 15 is currently amended, no claims are new and no claims are withdrawn. Claims 1-14, 23 and 26-28 are cancelled. Claims 15-22, 24-25 and 29 will be examined on the merits herein.
For clarity of the record, references to the instant specification herein use paragraph numbers from the Pre-Grant Publication US-20190194320-A1.
Response to Arguments
The Applicants’ arguments filed 10 Oct 2025 are acknowledged. For clarity, in this action, said arguments will be referred to as “Remarks” and the Non-Final Office Action mailed 22 May 2025 will be referred to as “NFOA.”
Objection(s) and Rejection(s) Withdrawn
The rejection of claims 15-22, 24-25 and 29 under 35 U.S.C. 112(b) related to the broad and narrow range (see NFOA par. 8-9) is withdrawn in view of the claim amendments and arguments.
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 § 112(b)
Claims 15-22, 24-25 and 29 remain 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 15, step (ii) claims “a plurality of isolated peptides having sequences that correspond to a plurality of potential epitopes on said protein”, but the term “correspond to” is not defined in the specification. The term is not defined in the specification, but the specification states “In some embodiments, the antigenic epitope is an antigenic epitope of TRPV1 that is based on the amino acid sequence of a surface exposed peptide that correlates with (or corresponds to) a calmodulin binding sequence of TRPV1 or the capsaicin binding site of TRPV1.” (pg. 33 ln. 32-35). The specification’s usage of “corresponds to” indicates that the two objects (the isolated peptide and the potential epitope, in the claim; the surface exposed peptide and the calmodulin binding sequence or capsaicin binding site in the specification) are not necessarily the same. Therefore, the claim is indefinite because one of ordinary skill in the art would not be able to determine the bounds of when a peptide “corresponds to” a epitope, and when it does not.
Response to Arguments
Applicant argues (Remarks pg. 4) that “At the very least within the context of the claim, it is submitted that it would be clear to the person skilled in the art that the phrase "plurality of isolated peptides having sequences that correspond to a plurality of potential epitopes on said protein" means that the isolated peptides have sequences of (or alternatively viewed that match the sequences of) the potential epitopes. … The fact that the specification also contains a sentence that also includes the term "corresponds to" in connection with certain other terms that are not used in the claims (i.e. in connection with the terms "surface exposed peptide" and "calmodulin binding sequence..." and "capsaicin binding site") does not render the use of the term "correspond to" in claim 15 unclear.”
This argument has been carefully considered but is not found persuasive. First, the examiner would be willing to accept applicant’s proposed definition that “that the isolated peptides have sequences of (or alternatively viewed that match the sequences of) the potential epitopes” as being a reasonable interpretation, if it were clearly stated for the record as being the intended scope of the claim. However, the Remarks’ statement is unclear whether applicant is proposing that “correspond to” means “comprising” (the isolated peptide has/includes the sequence of the potential epitope) or whether it means “consisting of” (the isolated peptide matches/is exactly the sequence of the potential epitope). It may be relevant that the examples in the instant specification do not show any antibodies raised against a protein consisting of the potential epitope; antibodies are only raised against proteins comprising the peptide and another protein component (“Synthetic peptides of aa96-117 and aa785-799 were linked to limpet hemocyanin (KLH) and further used to produce polyclonal antibodies” [0438]).
Applicant’s argument that one of ordinary skill in the art would not look to the specification to understand how a term is used because the sentence of the specification does not use the exact claim language is not found persuasive. No evidence or reasoning has been presented that the specification is using “corresponds to” to mean different things in those two situations.
Claim Rejections - 35 USC § 103
Claims 15-22, 24-25, and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Trkulja et al. (hereafter Paper IV; publicly available 24 Aug 2015; made of record in IDS filed 31 Jan 2023) in view of Trier et al. (8 Dec 2011; hereafter Trier; made of record in PTO-892 mailed 21 Sep 2023), Seubert et al. (WO-2014165271-A2; hereafter Seubert; made of record in PTO-892 mailed 31 Aug 2022), and Ounouna et al. (2002; hereafter Ounouna; PTO-892). The rejection of record is copied below; a response to arguments follows the rejection.
Regarding claims 15, Paper IV teaches “a method that selects [or identifies] antigen epitopes” that “are easily accessible to a mAb” (Abstract). Paper IV teaches “Proteoliposomes containing TRPV1 [i.e. a protein] were… subjected to limited proteolysis… using trypsin and Asp-N separately [i.e. one or more proteases]…. Digested peptides were then detected with liquid chromatography with tandem mass spectrometry (LC-MS/MS) [i.e. identifying sites at which one or more protease has cut said protein].” (pg. 4 “Epitope generation” section). Paper IV teaches generating isolated “synthetic peptides of aa96-117 and aa785-799” (pg. 5 par. 1), that these isolated peptides are overlapping cut sites and/or flanking within 50 amino acids of a cut site (Table 1 on pg. 5); however, these two synthetic peptides flank different cut sites, therefore Paper IV only teaches generating a single isolated peptide that overlaps or flanks a single given cut site.
The isolated synthetic peptides are “further used to produce polyclonal antibodies” (pg. 5 par. 1). As polyclonal antibodies contain a mixture of different antibody structures, this is considered to anticipate the limitation of generating multiple antibodies, though these antibodies bind to the single isolated peptide that overlaps or flanks a single cut site. Paper IV also teaches that their method is “compatible with conventional protocols for production of monoclonal antibodies” and suggests “using polyclonal antibodies as a first step to experimentally validate biological efficacy for several promising epitope candidates followed by production of monoclonal antibodies using the best epitope/epitopes…” (par. bridging pg. 8-9). Producing a polyclonal antibody and then a monoclonal antibody targeting the same isolated peptide would also anticipate the limitation of generating multiple antibodies.
Paper IV also teaches several experiments that probe the antibody against the full protein to identify whether the antibody binds to the expected epitope. Paper IV teaches probing each polyclonal antibody against the full-length protein (pg. 5-6 “Immunocytochemistry” section), which comprises a plurality of potential epitopes including potential epitopes corresponding to the isolated synthetic peptides. Paper IV also teaches performing functional assays that demonstrate the antibodies bind to specific known locations on the full protein by demonstrating that antibody binding interferes with specific functions known to involve those regions of the protein (pg. 7 “Electrophysiology” section). Therefore, as a result of the immunocytochemistry and functional experiments that probe the plurality of epitopes present on the full protein, Paper IV is able to identify that the antibodies bind to their expected epitopes.
Regarding claim 16-19, Paper IV teaches digestion “using trypsin and Asp-N separately” (pg. 4 “Epitope generation” section). This meets the limitations of using a single protease (per reaction) and also meets the limitation of using multiple proteases (in total).
Regarding claim 20, Paper IV demonstrates their method using “the human TRPV1 ion channel” which contains transmembrane domains (pg. 4 par. 3). The TRPV1 protein is present in a proteoliposome derived from CHO cells (pg. 4 “Epitope generation” section).
Regarding claim 21, Paper IV teaches “deriving proteoliposomes from cells and [immobilizing] them within the flow cell [to create] a stationary phase of membrane proteins” (pg. 2 par. 2). Specifically, Paper IV teaches the use of the LPI flow cell (pg. 4 “Epitope generation” section).
Regarding claim 22, “Digested peptides were then detected with liquid chromatography with tandem mass spectrometry (LC-MS/MS).” (pg. 4 “Epitope generation” section).
Regarding claim 24, the isolated “Synthetic peptides of aa96-117 and aa785-799” (pg. 5 par. 1), which correspond to potential epitopes, fall within 20 amino acids of the trypsin digestion cut sites at 96 and 798, respectively (see “start” and “stop” sites in Table 1 pg. 5).
Regarding claim 29, producing a monoclonal antibody corresponding to a validated polyclonal antibody, or generating multiple monoclonal antibodies specific to the same validated peptide, would generate a further antibody as required by claim 29.
Paper IV does not teach generating a plurality of isolated peptides that overlap with a single given cut site or are in a region that flanks a single given cut site, as in claim 15. Paper IV also does not teach that each of the plurality of potential epitopes, or at least a portion thereof, are within 50 or 20 amino acids of a cut site, as in claims 15 and 24 respectively, or are offset from another potential epitope by 1-3 amino acids, as in claim 25.
Regarding claim 15, Trier is a review relating to the “Production and characterization of peptide antibodies” (Title). Trier teaches that “synthetic peptides derived from the native protein are good alternatives for antibody production” and can be “easily produced to any peptide of choice” (Abstract). Trier teaches that the requirements for the peptide selected will vary depending on the intended use of the resulting antibody (pg. 137 col. 1 par. 3 and Table 1). Trier also teaches that peptides may not be immunogenic even if they are predicted to be antigenic by various algorithms (pg. 137 col. 1 par. 5). Trier teaches that antibodies can bind the full protein, including in the context of intact cells or a full organism (Table 3 pg. 143).
Regarding claims 15 and 24-25, Seubert teaches making monoclonal antibodies raised against multiple synthetic peptides from a single region of interest in a protein. “Agents used for active immunization can be the same types of immunogens used for generating monoclonal antibodies in laboratory animals, e.g., a peptide of 3-15 or 3-12 or 5-12, or 5-8 contiguous amino acids from a region of tau corresponding to residues 23-46, 25-44, 28-41 or 30-39 of SEQ ID NO. 1, such as, for example, a peptide including residues 28-30, 28-31, 28-32, 28-33, 28-34, 28-35, 28-36, 28-37, 28-38, 28-39, 28-40, 28-41, 29-31, 29-32, 29-33, 29-34, 29-35, 29-36, 29-37, 29-38, 29- 39, 29-40, 29-41, 30-32, 30-33, 30-34, 30-35, 30-36, 30-37, 30-38, 30-39, 30-40, 30-41, 31-33, 31-34, 31-35, 31-36, 31-37, 31-38, 31-39, 31-40, 31-41, 32-34, 32-35, 32-36, 32-37, 32-38, 32- 39, 32-40, 32-41, 33-35, 33-36, 33-37, 33-38, 33-39, 33-40, 33-41, 34-36, 34-37, 34-38, 34-39, 34-40, 34-41, 35-37, 35-38, 35-39, 35-40, 35-41, 36-38, 36-39, 36-40, 36-41 of SEQ ID NO: 1” [0093]. The peptides disclosed in Seubert include those offset by a single amino acid (for example, residues 28-30 and 28-31), or offset by two amino acids (for example, residues 23-26 and 25-44). Seubert also teaches exposing the protein to one or more proteases (one of trypsin, chymotrypsin, LysC or GluC) and identifying sites where the proteases cut the protein using mass spectrometry [0140]. The peptides of Seubert are in a region that overlaps or is within 50 amino acids of a single cut site (located at residues 25 and 44 of SEQ ID NO: 1, [0140]; the example peptides are all flanking the cut site at residue 25).
Regarding claims 15 and 29, Ounouna teaches making monoclonal antibodies raised against multiple synthetic peptides from a single region of interest in a protein (Abstract). Ounouna raised the antibodies against two overlapping peptides of different lengths (P19 and P11) that were derived from different protein variants and have different hydrophobicity (par. bridging pg. 490-491, illustrated in Figure 1 pg. 489). Ounouna raised polyclonal antibodies from three mice against each peptide, then chose strongly-reacting anti-P19 serum for hybridoma screening and monoclonal antibody generation (pg. 491 col. 1 par. 2). The result produced seven stable hybridomas, three secreting IgG1 antibodies and four secreting IgM antibodies (pg. 491 col. 1 par. 2). The different monoclonal antibodies had different binding strengths when tested against the P19 peptide used for immunization, and also had different epitopes as evidenced by only some of the antibodies binding to the overlapping P11 peptide (pg. 491 col. 1 par. 3, Table 2 on pg. 491). Ounouna also teaches probing the monoclonal antibody binding properties by contacting the monoclonal antibodies with full-length protein (pg. 491 par. bridging cols, Table 3 on pg. 491). The antibody binding to the peptide and full-length protein identifies that the epitope within the P19 peptide can be bound by the antibody.
One of ordinary skill in the art at the time of filing would consider it prima facie obvious to improve the method of Paper IV by generating multiple isolated peptides that overlap or flank a single cut site (instead of a single isolated peptide), using the multiple isolated peptides to generate multiple polyclonal antibody preparations (instead of antibody preparations raised against said single isolated peptide), and probe the protein with the resulting multiple antibody preparations raised against a single isolated peptide, thereby arriving at the claimed invention, because it was well known in the field at the time of filing to choose different types of peptide (different length, etc.) surrounding the same region of interest, as taught in Seubert, and Ounouna, because the peptides will not necessarily be equally immunogenic and the resulting antibodies can have different properties that make them useful in different applications, as taught in Trier and Ounouna. Therefore, the combination would be desirable in order to make antibodies for different situations and/or to ensure that at least one of the peptides will be antigenic and capable of producing large titres of antibody. See MPEP 2144(II): “The strongest rationale for combining references is a recognition, expressly or impliedly in the prior art … that some advantage or expected beneficial result would have been produced by their combination.”
Also, generating a plurality of antibody preparations using a plurality of isolated peptides, and then testing the resulting antibodies to confirm their ability to bind to the protein, instead of generating a single antibody preparation using a single isolated peptide and confirming it binds to the protein, appears to be merely a difference of degree. One of ordinary skill in the art would find it obvious to optimize the number of times they perform the step of generating an isolated peptide and corresponding polyclonal and/or monoclonal antibody because Trier and Ounouna teach that a single peptide may not be antigenic, and that different antibodies can have different structures (for example, IgG versus IgM), specificity, and affinity/avidity characteristics. This optimization requires only using routine experimentation by merely repeating the polyclonal and/or monoclonal antibody generation steps disclosed in Paper IV, and Ounouna and Seubert collectively teach that it is a standard procedure in the field to make monoclonal antibodies using multiple peptides around a single region of interest. See MPEP 2144.05.II, and particularly its citation of In re Williams, 36 F.2d 436, 438 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.").
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that combining prior art elements according to known methods to yield predictable results, is obvious unless its application is beyond that person's skill. KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007) also discloses that the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results. In the instant case, all elements were known in the art. Specifically, the art teaches: identifying sites at which a protease cuts a protein after limited proteolysis, taught by Paper IV; generating an isolated peptide that overlaps or flanks a single protease cut site, taught by Paper IV and Seubert; generating polyclonal and monoclonal antibodies that bind isolated peptides, taught by Paper IV, Trier, Ounouna, and Seubert; raising antibodies against multiple peptides near a region of interest, taught by Ounouna and Seubert, and probing the full-length protein with antibodies, taught by Paper IV, Trier, and Ounouna. In addition, combining these elements yields a method wherein each element merely performs the same function as it does separately; thus the results of the combination would be recognized as predictable to one of ordinary skill in the art. Therefore, the claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Response to Arguments
Applicant argues (Remarks pg. 5-6) that Paper IV showed that both antibodies are biologically active, so “the skilled person would have lacked any motivation from Paper IV to seek further, alternative, TRPV1 epitopes to target with antibodies, let alone additional epitopes that are in the vicinity of the same cut sites upon which the OTV1 and OTV2 antibody epitopes are based. … There is no suggestion in Paper IV to do so. Thus, it would not have been prima facie obvious from Paper IV (the primary reference) to do so. Even if the skilled person "could" improve the method of Paper IV as the Examiner has suggested, they "would not" have done so because there would have been no motivation to do so.”
This argument has been carefully considered but is not found persuasive. In response to applicant's arguments against the references individually (“it would not have been prima facie obvious from Paper IV (the primary reference) to do so”), 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). The examiner agrees that Paper IV does not include a teaching to seek further, alternative, TRPV1 epitopes that are in the vicinity of the same cut sites upon which the OTV1 and OTV2 antibody epitopes are based; this is inherent in the rejection as non-obvious rather than non-novel.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, the claim is not limited to a method that identifies TRPV1 epitopes, it claims a method that can be used on any protein. The arguments do not persuasively explain why one of ordinary skill in the art would take the success of Paper IV at raising functional antibodies against TRPV1 to mean that the method, when used on any possible protein, would raise an optimal antibody for every possible purpose using the first attempted isolated peptide, i.e. no motivation to make more than one peptide or antibody in the method as claimed. In contrast to the applicant’s argument, the art shows that it was well known that different peptides and different antibodies have different properties, so “the combination would be desirable in order to make antibodies for different situations and/or to ensure that at least one of the peptides will be antigenic and capable of producing large titres of antibody” (par. 26).
Also, in KSR and other cases, the courts have found that “In determining obviousness, neither the particular motivation to make the claimed invention nor the problem the inventor is solving controls. The proper analysis is whether the claimed invention would have been obvious as of the relevant time to one of ordinary skill in the art after consideration of all the facts. … obviousness analysis is not "confined by a formalistic conception of the words teaching, suggestion, and motivation." Intel Corp. v. Qualcomm Inc., 21 F.4th 784, 795, 2021 USPQ2d 1259 (Fed. Cir. 2021) (quoting KSR, 550 U.S. at 419, 82 USPQ2d at 1396).” (quoted from MPEP 2141). The rejection of record also noted that the modification would be obvious using KSR rationales that combining prior art elements according to known methods to yield predictable results, is obvious unless its application is beyond that person's skill and the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results (par. 28), and quotes In re Williams’s argument that a change of degree (optimizing the number of times they perform the step of generating an isolated peptide and corresponding polyclonal and/or monoclonal antibody) does not make a patent non-obvious (par. 27). Applicant does not argue against either of these reasons that one of ordinary skill would find the required modification obvious.
Applicant argues (Remarks pg. 6) that “Although multiple peptides from a single region of a protein are listed in paragraph [0093] of Seubert, there is no suggestion or motivation in Seubert to use more than one (i.e. a plurality) of these peptides to generate antibodies; they are simply presented as a list of alternative peptides to use.” Therefore, “the skilled person consulting Seubert would not be led to an improved version of the Paper IV method”.
This argument has been carefully considered but is not found persuasive. The examiner disagrees with this characterization of Seubert. The sentence quoted in the rejection (see NFOA par. 22 and par. 24) refers to “Agents used for active immunization” (note the plural) and the subsequent sentence in Seubert refers to “inducing antibodies binding to the same or overlapping epitope as 16B5” (emphasis added, i.e. using multiple isolated peptides to induce antibodies that bind to overlapping sites on the protein). Applicant has not pointed to any teachings in Seubert indicating that these peptides are alternatives, or any teachings in Seubert to only use one peptide to raise antibodies. A review of the reference also did not identify any teachings to not use multiple peptides to raise antibodies. Therefore, applicant has not convincingly argued that the examiner’s interpretation of Seubert is incorrect; the examiner remains of the opinion that Seubert teaches that all of the disclosed synthetic peptides can be used to raise antibodies rather than being presented as strictly alternatives.
This argument against Seubert alone also does not fully address how Seubert is used in the rejection of record. Seubert is not used to identify specific peptide(s) that should be used to raise antibodies. Instead, Seubert is used in combination with the Ounouna and Trier references to show the state of the art, specifically to show that “it was well known in the field at the time of filing to choose different types of peptide (different length, etc.) surrounding the same region of interest, as taught in Seubert, and Ounouna, because the peptides will not necessarily be equally immunogenic and the resulting antibodies can have different properties that make them useful in different applications, as taught in Trier and Ounouna” (NFOA par. 24 and par. 26 above) and that “Ounouna and Seubert collectively teach that it is a standard procedure in the field to make monoclonal antibodies using multiple peptides around a single region of interest” (NFOA par. 25 and par. 27 above). 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). The argument is not persuasive because it does not address the examiner’s position about how well-known the process of raising antibodies against multiple peptides is within the art at the time of filing.
Applicant argues (Remarks pg. 6-7) “In Ounouna, although two different peptides are used for antibody generation (P19 and P11- see the "peptide immunogens" section on page 489) and these two peptides have a six amino acid stretch in common with each other (EQGSIQ - see the final two rows of Figure 1), it is evident that these two peptides correspond to potential epitope sequences from two different proteins (see Figure 1). In this regard, P19 has an amino acid sequence that corresponds to a portion of a protein from the PVY-P21 virus, and P11 has an amino acid sequence that corresponds to a portion of a different protein sequence, a protein from the PVY-P2 virus (see the "peptide immunogens" section on page 489 and Figure 1). Thus, Ounouna does not teach or suggest "to choose different types of peptide (different length, etc.) surrounding the same region of interest" of a single given protein as per claim 15. There is also no motivation to do so.”
This argument has been carefully considered but is not found persuasive. The examiner disagrees with this characterization of Ounouna teaching using peptides from two different proteins. For clarity of the record, the phrase “a single given protein” is not found in the currently presented claim 15. The peptides must overlap with “a single given cut site” (which identifies a site of interest in the rejection being argued), on “a protein”. Ounouna studied Potato virus Y coat protein (Title) and Figure 1 shows the sequences of the same coat protein from seven Potato virus Y (PVY) isolates (see Figure 1 legend). Isolate-to-isolate sequence variation does not change that both peptides are from the Potato virus Y coat protein. Also, Ounouna was clearly interested in the P11 peptide as it related to the shared epitope from P19 because antibodies were only generated if they bound to the P19 peptide: “Ounouna raised polyclonal antibodies from three mice against each peptide, then chose strongly-reacting anti-P19 serum for hybridoma screening and monoclonal antibody generation” (NFOA par. 45 and par. 25 above). So the examiner remains of the opinion that Ounouna teaches “to choose different types of peptide (different length, etc.) surrounding the same region of interest” on a single protein, the Potato virus Y coat protein.
Also, this argument against Ounouna alone is not persuasive because it does not address how the reference is used in the rejection of record. Ounouna is not used to identify specific peptide(s) that should be used to raise antibodies. Instead, Ounouna is used in combination with the Seubert and Trier references to show the state of the art, specifically to show that “it was well known in the field at the time of filing to choose different types of peptide (different length, etc.) surrounding the same region of interest, as taught in Seubert, and Ounouna, because the peptides will not necessarily be equally immunogenic and the resulting antibodies can have different properties that make them useful in different applications, as taught in Trier and Ounouna” (NFOA par. 24 and par. 26 above), and that “Trier and Ounouna teach that a single peptide may not be antigenic, and that different antibodies can have different structures (for example, IgG versus IgM), specificity, and affinity/avidity characteristics”, “Ounouna and Seubert collectively teach that it is a standard procedure in the field to make monoclonal antibodies using multiple peptides around a single region of interest” (NFOA par. 25 and par. 27 above). 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). The argument is not persuasive because it does not address the examiner’s position about how well-known the process of raising antibodies against multiple peptides is within the art at the time of filing.
Applicant’s argument is also not persuasive because it relies on an improperly narrow view of the claim language used to define the isolated peptides. The currently presented claims require that the isolated peptides “hav[e] sequences that correspond to a plurality of potential epitopes”. The broadest reasonable interpretation of this term is that the peptides must comprise the sequences that correspond to the epitopes. Therefore, the P19 peptide comprises a longer sequence from the coat protein from the PVY-P21 virus, and the P11 peptide comprises a shorter sequence (shown in bold in Figure 1 and reproduced below with highlighting) also from the coat protein from the PVY-P21 virus. As quoted above, Ounouna was clearly interested in the portion of the P11 peptide that is the shared epitope from P19, because that is what was used to screen the resulting antibodies. In the interest of compact prosecution, the argument would still not be persuasive if the claim were amended so that the claim scope reflected applicant’s arguments due to the other reasons above.
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Modified Figure 1 from Ounouna, highlighted regions in P19 and P11 show the isolated peptides each have sequences that correspond to different length epitopes on the PVY-P21 protein.
Applicant argues (Remarks pg. 7-8) that “Trier is simply a general review article relating to peptide antibodies. Although Trier discusses various considerations around the generation of peptide antibodies, there is no suggestion to use multiple (a plurality of) isolated peptides that correspond to multiple (a plurality of) potential epitopes in a region of interest (let alone in a region overlapping a cut site or within 50 amino acids of said cut site as per present claim 15) to generate antibodies and then to test the antibodies generated for binding to a full-length protein. The Examiner refers to Table 3 of Trier as teaching that antibodies can bind "the full protein". However, this is merely a Table summarizing various standard end uses of peptide antibodies; there is no disclosure or suggestion in Trier to test for binding on a full protein in the context of a method of identifying an epitope as currently claimed.”
This argument has been carefully considered but is not found persuasive. This argument that Trier does not suggest using multiple (a plurality of) isolated peptides that correspond to multiple (a plurality of) potential epitopes in a region of interest does not address how Trier is used in the rejection of record. Trier is not used to identify specific peptide(s) that should be used to raise antibodies. Instead, Trier is used in combination with the Ounouna and Seubert references to show the state of the art, specifically to show that “it was well known in the field at the time of filing to choose different types of peptide (different length, etc.) surrounding the same region of interest, as taught in Seubert, and Ounouna, because the peptides will not necessarily be equally immunogenic and the resulting antibodies can have different properties that make them useful in different applications, as taught in Trier and Ounouna” (NFOA par. 24 and par. 26 above) and that “Trier and Ounouna teach that a single peptide may not be antigenic, and that different antibodies can have different structures (for example, IgG versus IgM), specificity, and affinity/avidity characteristics” (NFOA par. 25 and par. 27 above). 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). The argument is not persuasive because it does not address the examiner’s position about how well-known the process of raising antibodies against multiple peptides is within the art at the time of filing.
The argument that Trier does not suggest testing for binding on a full protein in the context of a method of identifying an epitope is not relevant because this is a step that is taught in Paper IV (see NFOA par. 13 and par. 15 above) and it is not a modification that needs to be made to arrive at the claimed invention. However, the argument is also confusing because applicant has not explained how the step of probing the protein with antibodies would be different in a method of identifying an epitope compared to when an antibody-protein binding step is performed for another intent. If applicant wishes the step to be more detailed to differentiate step (iii) from antibody-protein interaction steps that are “standard end uses” (Remarks pg. 8), the claim should be clarified.
Applicant argues (Remarks pg. 8) that “Applicant does not believe they [the skilled person] would consider consulting the disparate selection of other documents that the Examiner has cited. In this regard, Seubert is a patent document in the field of tau immunotherapy, Ounouna relates to monoclonal antibodies against Potato Virus Y coat protein for the purposes of PVY strain differentiation, and Trier is merely a general review article on the subject of peptide antibodies.”
This argument has been carefully considered but is not found persuasive. In response to applicant's argument that Seubert, Ounouna, and Trier are nonanalogous art (“disparate selection of other documents”), it has been held that a prior art reference must either be in the field of the inventor’s endeavor or, if not, then be reasonably pertinent to the particular problem with which the inventor was concerned, in order to be relied upon as a basis for rejection of the claimed invention. See In re Oetiker, 977 F.2d 1443, 24 USPQ2d 1443 (Fed. Cir. 1992). In this case, the claims are methods of generating antibodies and are not limited to any particular protein antigen. The instant specification confirms the generality by stating “The present invention relates to certain new methods to select epitopes of target proteins, utilized for, but not limited to, antibody (e.g. functional antibody) generation. The present invention thus relates in some aspects to a method for generating an antibody.” [0001, emphasis added]. Seubert and Ounouna both disclose methods that generate antibodies (see NFOA par. 22-23 and par. 24-25 above) and are in the field of the inventor’s endeavor. Applicant admits that Trier is a review article on the subject of peptide antibodies (Remarks pg. 8), and therefore is also in the field of generating antibodies like the inventor’s endeavor. Therefore, the Seubert, Ounouna, and Trier references are analogous art that can be properly used in a 103 rejection.
Applicant argues (Remarks pg. 8) that “it seems that the four document § 103 rejection has been formulated using inappropriate hindsight / ex post facto knowledge of the present invention, "cherry picking" certain disclosures from each document, and asserting that putting all of these together would obviously lead to the invention as presently claimed.”
This argument has been carefully considered but is not found persuasive. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). The Seubert, Ounouna and Trier references are collectively used to show the state of the art at the time of filing (see par. 26-27 above). The decision that the modification is obvious is based on the state of the art and the level of ordinary skill at the time of filing, as shown in those references.
Double Patenting
Claims 15-22, 24-25, and 29 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-35 of U.S. Patent No. 11,912,765 in view of Trier et al. (8 Dec 2011; hereafter Trier; made of record in PTO-892 mailed 21 Sep 2023), Seubert et al. (WO-2014165271-A2; hereafter Seubert; made of record in PTO-892 mailed 31 Aug 2022), and Ounouna et al. (2002; hereafter Ounouna; PTO-892). The rejection of record is copied below; a response to arguments follows the rejection.
Regarding instant claims 15, 22, and 29, ‘765 claim 1 recites a method comprising (i) exposing the protein to limited or restricted proteolysis, and ‘765 claims 31-32 recite that cleaved-off peptides may be identified. Such an identification would identify where the peptides ended, and therefore identify where the protein had been cut by the protease treatment, as is required by step (i) of instant claim 15. ‘765 claim 1 also recites a step of (iii) raising an antibody against the antigenic epitope, and ‘765 claim 7 teaches constructing an antigenic epitope (i.e. generating an isolated peptide) based on the surface-exposed peptide and raising an antibody against said antigenic epitope. ‘765 claim 1 states that surface-exposed peptides are defined as being cleaved off by the action of the protease, so the constructed epitope/peptide must be immediately adjacent to a cut site. ‘765 claim 35 states that the antibody can be polyclonal or monoclonal. As this rejection relies upon the teachings of ‘765 claim 1, it is noted that all other claims depend from claim 1 and therefore also recite these features.
Regarding instant claim 16, ‘765 claim 9 recites that a single protease is used to digest the protein.
Regarding instant claim 17, ‘765 claim 10 recites that multiple proteases are used to digest the protein.
Regarding instant claims 18-19, ‘765 claim 13 recites that the protease is selected from a list of proteases that is identical to instant claim 18 and includes all proteases recited in instant claim 19.
Regarding instant claim 20, ‘765 claim 15 recites that the protein is a membrane protein that is present in a proteoliposome derived from cells
Regarding instant claim 21, ‘765 claim 16 recites that the proteoliposome is immobilized in a flow cell to create a stationary phase of membrane proteins.
Regarding instant claim 22, ‘765 claims 31-32 recite that the peptides may be identified by mass spectrometry or specifically LC-MS/MS.
Regarding claim 24, ‘765 claim 7 teaches constructing an antigenic epitope (i.e. generating an isolated peptide) based on the surface-exposed peptide and raising an antibody against said antigenic epitope. ‘765 claim 1 states that surface-exposed peptides are defined as being cleaved off by the action of the protease, so the constructed epitope/peptide must be immediately adjacent to a cut site.
The claims of ‘765 do not teach generating a plurality of isolated peptides that overlap with a single given cut site or are in a region that flanks a single given cut site, as required by claim 15 part (ii), or probing a plurality of potential epitopes with antibodies, as required by claim 15 part (iii). The claims of ‘765 also do not teach that each of the plurality of potential epitopes are within 20 amino acids of a cut site, as required by claim 24, or are offset from another potential epitope by 1-3 amino acids, as required by claim 25, or that the process of generating a monoclonal antibody involves generating a further antibody, as required by claim 29.
Regarding claim 15, Trier is a review relating to the “Production and characterization of peptide antibodies” (Title). Trier teaches that “synthetic peptides derived from the native protein are good alternatives for antibody production” and can be “easily produced to any peptide of choice” (Abstract). Trier teaches that the requirements for the peptide selected will vary depending on the intended use of the resulting antibody (pg. 137 col. 1 par. 3 and Table 1). Trier also teaches that peptides may not be immunogenic even if they are predicted to be antigenic by various algorithms (pg. 137 col. 1 par. 5). Trier teaches that antibodies can bind the full protein, even in the context of intact cells or a full organism (Table 3 pg. 143).
Regarding claims 15 and 24-25, Seubert teaches making monoclonal antibodies raised against multiple synthetic peptides from a single region of interest in a protein. “Agents used for active immunization can be the same types of immunogens used for generating monoclonal antibodies in laboratory animals, e.g., a peptide of 3-15 or 3-12 or 5-12, or 5-8 contiguous amino acids from a region of tau corresponding to residues 23-46, 25-44, 28-41 or 30-39 of SEQ ID NO. 1, such as, for example, a peptide including residues 28-30, 28-31, 28-32, 28-33, 28-34, 28-35, 28-36, 28-37, 28-38, 28-39, 28-40, 28-41, 29-31, 29-32, 29-33, 29-34, 29-35, 29-36, 29-37, 29-38, 29- 39, 29-40, 29-41, 30-32, 30-33, 30-34, 30-35, 30-36, 30-37, 30-38, 30-39, 30-40, 30-41, 31-33, 31-34, 31-35, 31-36, 31-37, 31-38, 31-39, 31-40, 31-41, 32-34, 32-35, 32-36, 32-37, 32-38, 32- 39, 32-40, 32-41, 33-35, 33-36, 33-37, 33-38, 33-39, 33-40, 33-41, 34-36, 34-37, 34-38, 34-39, 34-40, 34-41, 35-37, 35-38, 35-39, 35-40, 35-41, 36-38, 36-39, 36-40, 36-41 of SEQ ID NO: 1” [0093]. The peptides disclosed in Seubert include those offset by a single amino acid (for example, residues 28-30 and 28-31), or offset by two amino acids (for example, residues 23-26 and 25-44). Seubert also teaches exposing the protein to one or more proteases (one of trypsin, chymotrypsin, LysC or GluC) and identifying sites where the proteases cut the protein using mass spectrometry [0140]. The peptides of Seubert are in a region that overlaps or is within 50 amino acids of a single cut site (located at residues 25 and 44 of SEQ ID NO: 1, [0140]; the example peptides are all flanking the cut site at residue 25).
Regarding claims 15 and 29, Ounouna teaches making monoclonal antibodies raised against multiple synthetic peptides from a single region of interest in a protein (Abstract). Ounouna raised the antibodies against two overlapping peptides of different lengths (P19 and P11) that were derived from different protein variants and have different hydrophobicity (par. bridging pg. 490-491, illustrated in Figure 1 pg. 489). Ounouna raised polyclonal antibodies from three mice against each peptide, then chose strongly-reacting anti-P19 serum for hybridoma screening and monoclonal antibody generation (pg. 491 col. 1 par. 2). The result produced seven stable hybridomas, three secreting IgG1 antibodies and four secreting IgM antibodies (pg. 491 col. 1 par. 2). The different monoclonal antibodies had different binding strengths when tested against the P19 peptide used for immunization, and also had different epitopes as evidenced by only some of the antibodies binding to the overlapping P11 peptide (pg. 491 col. 1 par. 3, Table 2 on pg. 491). Ounouna also teaches probing the monoclonal antibody binding properties by contacting the monoclonal antibodies with full-length protein (pg. 491 par. bridging cols, Table 3 on pg. 491). The antibody binding to the peptide and full-length protein identifies that the epitope within the P19 peptide can be bound by the antibody.
One of ordinary skill in the art at the time of filing would consider it prima facie obvious to improve the method of ‘765 by generating multiple isolated peptides that overlap or flank a single cut site (instead of a single isolated peptide), using the multiple isolated peptides to generate multiple polyclonal antibody preparations (instead of antibody preparations raised against said single isolated peptide), and probe the protein with the resulting multiple antibody preparations raised against a single isolated peptide, thereby arriving at the claimed invention, because it was well known in the field at the time of filing to choose different types of peptide (different length, etc.) surrounding the same region of interest, as taught in Seubert, and Ounouna, because the peptides will not necessarily be equally immunogenic and the resulting antibodies can have different properties that make them useful in different applications, as taught in Trier and Ounouna. Therefore, the combination would be desirable in order to make antibodies for different situations and/or to ensure that at least one of the peptides will be antigenic and capable of producing large titres of antibody. See MPEP 2144(II): “The strongest rationale for combining references is a recognition, expressly or impliedly in the prior art … that some advantage or expected beneficial result would have been produced by their combination.”
Also, generating a plurality of antibody preparations using a plurality of isolated peptides, and then testing the resulting antibodies to confirm their ability to bind to the protein, instead of generating a single antibody preparation using a single isolated peptide and confirming it binds to the protein, appears to be merely a difference of degree. One of ordinary skill in the art would find it obvious to optimize the number of times they perform the step of generating an isolated peptide and corresponding polyclonal antibody because Trier and Ounouna teach that a single peptide may not be antigenic, and that different antibodies can have different structures (for example, IgG versus IgM), specificity, and affinity/avidity characteristics. This optimization requires only using routine experimentation by merely repeating the antibody generation step disclosed in ‘765, and Ounouna and Seubert collectively teach that it is a standard procedure in the field to make monoclonal antibodies, as taught in ‘765, using multiple peptides around a single region of interest. See MPEP 2144.05.II, and particularly its citation of In re Williams, 36 F.2d 436, 438 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.").
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that combining prior art elements according to known methods to yield predictable results, is obvious unless its application is beyond that person's skill. KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007) also discloses that the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results. In the instant case, all elements were known in the art. Specifically, the art teaches: identifying sites at which a protease cuts a protein after limited proteolysis, taught by ‘765; generating an isolated peptide/epitope that overlaps or flanks a single protease cut site, taught by ‘765 and Seubert; generating polyclonal and monoclonal antibodies that bind isolated peptides, taught by ‘765, Trier, Ounouna, and Seubert; raising antibodies against multiple peptides near a region of interest, taught by Ounouna and Seubert, and probing the full-length protein with antibodies, taught by Trier, and Ounouna. In addition, combining these elements yields a method wherein each element merely performs the same function as it does separately; thus the results of the combination would be recognized as predictable to one of ordinary skill in the art. Therefore, the claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Response to Arguments
Applicant argues (Remarks pg. 8-9) that “a combination of the teachings of Trier with the claims of the '765 patent would not have resulted in the invention as recited in cited claims 15-22, 24, 25 and 29 as neither the claims of the '765 patent nor Trier discloses (or suggests) probing a protein for the presence of potential epitopes, where the potential epitopes overlap with a single given cut site or are within 50 amino acids of a single given cut site in accordance with step (iii) of claim 15 as amended herein. Although Trier discusses various considerations around the generation of peptide antibodies, there is no suggestion to use multiple (a plurality of) isolated peptides that correspond to multiple (a plurality of) potential epitopes in a region of interest (let alone in a region overlapping a cut site or within 50 amino acids of said cut site as per present claim 15) to generate antibodies and then to test the antibodies generated for binding to a full-length protein.”
These arguments have been carefully considered but are not found persuasive. 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 arguments about “a combination of the teachings of Trier with the claims of the '765 patent” is not relevant to the instant rejection of the claims of the '765 patent in combination with the teachings of Trier, and Seubert, and Ounouna. For completeness of the record, the argument that there is no suggestion in the art to perform the modification was addressed and not found persuasive in the similar 103 rejection above (see par. 30-33).
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/AMELIA NICOLE DICKENS/Examiner, Art Unit 1645
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674