DETAILED ACTION
Status of Application, Amendments and/or Claims
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . The claim listing filed on 3/17/26 has been entered; no amendments are indicated. Claims 1-31, 34-44 and 46 are pending.
Election/Restrictions
Applicants’ election of Group I, claims 1-31 and 34, in the reply filed on 3/17/16 is acknowledged. There is no indication of whether the election is with or without traverse, but because the response did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.03(a)). Claims 35-44 and 46 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Applicants were also required, in reply to the restriction requirement mailed on 1/27/26, to elect a single species of (1) target antigen and (2) polymer/other antigen/oligopeptide polyhistidine (page 7). The requirements for each required selection of (i) a number of polyhistidine residues and (ii) target antigen source or fusion protein partner. In the 3/17/26 reply, Applicants merely indicates “6 histidines” and “HLA”. However, as each set of species encompasses these selections, they are constructively interpreted to apply to each species election. Claims 4, 13-15, 24 and 28-30 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claims 1-3, 5-12, 16-27, 31 and 34 are under consideration, as they read upon the elected species.
Drawings
Corrected drawings in compliance with 37 CFR 1.121(d) are required because the drawings do not comply with 37 C.F.R. 1.84(U)(1), which states that partial views of a drawing which are intended to form one complete view, whether contained on one or several sheets, must be identified by the same number followed by a capital letter. Specifically, Figure 1 as filed on 8/2/23 is presented on two sheets, labeled "FIG. 1" and "FIG. 1 (Continued)". These two sheets should be relabeled as "FIG. 1A" and "FIG. 1B".
Applicants are reminded that once the drawings are changed to meet the separate numbering requirement of 37 C.F.R. 1.84(U)(1), Applicants are required to file an amendment to change the Brief Description of the Drawings and the rest of the specification accordingly.
Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). Applicants are advised to employ the services of a competent patent draftsperson outside the Office, as the USPTO no longer prepares new drawings. The corrected drawings are required in reply to the Office action to avoid abandonment of the application. The requirement for corrected drawings will not be held in abeyance.
Specification
The disclosure is objected to because of the following informalities:
---The title is not descriptive because it is directed generally to any method for improved immunoassays with synthetic antigens, whereas the claimed method is limited to use of histidine polymers to remove anti-poly-histidine antibodies. A new title is required that is clearly indicative of the claimed. The following title is suggested: “Methods and Materials for Improved Immunoassays Using Synthetic Antigens by Removing Anti-Poly-Histidine Antibodies with Histidine Polymers”.
---The disclosure is objected to because it contains an embedded hyperlink (browser-executable code) in the second line of page 2 (part of ¶ 5). Applicant is required to remove the embedded hyperlink; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01 (VII).
--On pages 2 (¶ 5), 6 (¶ 21) and 7 (¶ 26), the term “Human leukocyte antigens (HLA)” should have each word capitalized, i.e., ““Human Leukocyte Antigens (HLA)”. Compare with the usage on page 4, ¶ 13 of the specification. Likewise, on page 2 (¶ 5), the term “Swine leukocyte antigens (SLA)” should be written as “Swine Leukocyte Antigens (SLA”).
---The Brief Description of Figure 1 on page 8, ¶ 32, must be amended to refer to Figures 1A and 1B as set forth above in “Drawings”.
Appropriate correction is required.
Claim Objections
Claims 16, 20-22 and 31 are objected to because of the following informalities:
In each of claims 16 and 31, each word of “Human leukocyte antigen” should be capitalized, i.e., “Human Leukocyte Antigen”, as on page 4, ¶ 13 of the specification.
In claim 20, line 3, “a target antigen protein” should be “the target antigen”. Compare with claim 11, line 2, which recites, “the target antigen”.
In claim 20, line 4, “C-terminal” should be “C-terminal end” or “C-terminus”. Compare with claim 11, which uses “C-terminal end”.
The remaining claim(s) are objected to for depending from an objected claim.
Appropriate correction is required.
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 2-3, 5, 8-12, 17-27, 31 and 34 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 pre-AIA the applicant regards as the invention.
Claims 2-3, 8-12, 18-20, 22, 24 and 27 each refer to a number (“at least two” or “at least six”) of “contiguous histidine peptides”, but the number of required histidines is unclear due to the use of the term “peptides”, which refers to two or more amino acids that are linked by a bond. For example, it is unclear whether “at least six contiguous histidine peptides” refers to six contiguous histidine amino acids or six contiguous histidine peptides of indeterminate length (i.e., at least 12 histidines if the minimum number of histidines in the peptide is two). It appears that the former is intended, and if so, the claim could be rendered definite by amending to the claims to recite, “contiguous histidine amino acids”.
Claim 5 recites the limitation “the recombinant poly-histidine sequence target antigen” in lines 1-2. There is insufficient antecedent basis for this limitation in the claim. Specifically, claim 5 depends from claim 2, which in turn depends from claim 1. Neither claim 1 or 2 recites that the target antigen is recombinant. As such, this limitation lacks antecedent basis in the parent claims. In this regard, the claim could be rendered definite by amending it to depend from claim 3, which does further limit the target antigen to one that is recombinantly produced.
Claims 10, 11 and 20 each recites the limitation “the histidine polymer” in line 1. There is insufficient antecedent basis for this limitation in the claim. Specifically, these claims depend from claim 1, which refers to “histidine polymers” (plural), but not “histidine polymer” (singular). As such, the use of the term in the singular does not find antecedent basis in the parent claim.
Claim 17 recites the limitation “the serum sample” in line 6. There is insufficient antecedent basis for this limitation in the claim. Specifically, this independent claim contains earlier reference to “a biological sample” (line 4) but not “a serum sample”, and thus the use of “the serum sample” does not find antecedent basis earlier in the claim.
Claim 21 recites the limitation “the serum sample” in line 6. There is insufficient antecedent basis for this limitation in the claim. Specifically, this claim depends from claims 20 and 17, the latter of which recites “a biological sample” (line 4) but not “a serum sample”, and thus the use of “the serum sample” does not find antecedent basis earlier in the claim.
The remaining claim(s) included in the rejection are dependent claims that depend from one of the claims rejected above, and encompass the same indefinite subject matter.
Note on Prior Art Rejection(s)
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
(1) Claims 1-3, 5-12, 17-23 and 25-27 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Pinter et al, U.S. Patent Application Publication 20030105282, published 6/6/03, filed 1/2/02, and claiming priority to 9/8/98. The earliest date to which the instant application claims priority is 2/3/21.
Claim 1 encompasses a method of screening a biological sample for antibodies that specifically bind a target antigen by (1) obtaining said sample from a subject; (2) subjecting said sample to histidine polymers to remove anti-poly-histidine antibodies; (3) contacting said target antigen with said sample; and (4) detecting binding of antibodies in said sample to said target antigen.
Pinter teaches a “Case-A2 fusion protein” that contains “the V1/V2 domain of gp120” by joining “residues 111-206 of the gp120 protein of the Case A2 isolate of HIV-1” to “residues 1-263 of MuLV gp70 protein”. The protein further contains “a His6 affinity tag” inserted “into residues 1-263 of MuLV gp70” (¶ 50). Pinter further teaches a method comprising: (1) obtaining a biological sample (serum) sample from an individual (a rat immunized with Case A2 fusion protein comprising gp70 with an inserted His6 tag) (¶ 54-55); (2) subjecting said sample to histidine polymers in order to remove anti-poly-histidine antibodies (“p621, a recombinant protein containing only the gp70-derived sequences (including the 6His tag) present in the fusion protein, to remove the irrelevant anti-gp70 antibodies” (¶ 61); (3) contacting the sample with a target antigen) Case A2 fusion protein) (¶ 61), and (4) detecting binding of antibodies in said sample to the target antigen (“The eluted antibodies were then analyzed for antigen specificity”; ¶ 62). Thus, the sample was screened with a gp70-6His fusion proteins, which comprise a 6His tag, which meets the limitation of “histidine polymers”, and the 6His portion of such would inherently bind and block or remove anti-polyhistidine antibodies in the serum sample. As such, the teachings of Pinter anticipate claim 1.
Claims 2, 3 and 5 encompass a method of claim 1 wherein the target antigen is a synthetic antigen comprising at least six contiguous histidines (claim 2) that is a recombinantly produced (claim 3) or produced by a mammalian expression system (claim 5). The target antigen of Pinter (the Case A2 fusion protein) comprises a 6His tag, which has six contiguous histidines, and Pinter further teaches that the proteins of the invention were expressed in CHO cells (¶ 51). As such, the teachings of Pinter also anticipate claims 2, 3 and 5.
Claim 6 encompasses a method of claim 1 wherein the biological sample is obtained from a human subject. Pinter further teaches that the method of making antibodies includes “immunizing a mammalian subject” (¶ 12) and further than mammalian subjects include humans (¶ 90). As such, the teachings of Pinter also encompass claim 6.
Claim 7 encompasses a method of claim 1 wherein the sample is a serum sample. In the teachings of Pinter set forth above, the sample is a serum sample. As such, the teachings of Pinter also anticipate claim 7.
Claims 8 and 9 encompass a method of claim 1 wherein the histidine polymers comprise at least six contiguous histidines. In the teachings of Pinter set forth above, the “histidine polymers” are p621 proteins (gp70 comprising 6His), which comprises 6 contiguous histidines. As such, the teachings of Pinter also anticipate claims 8 and 9.
Claims 10-12 encompass a method of claim 1 wherein the histidine polymers comprises a fusion of a recombinant protein with at least two histidines (claim 10) and further comprising a C-terminal truncated version of the target antigen having the at least two contiguous histidines at its C-terminal end (claim 11) or comprising at least 5 contiguous histidines (claim 12). As set forth above, the histidine polymers of Pinter are fusion proteins including gp70-derived sequences and a His6 tag, which comprises 6 contiguous histidines. Pinter further teaches that the His6 tag was inserted by “replacing the Q residues at position 9” (¶ 51). As this sequence is inserted into the gp70 sequence, it is C-terminal to a portion of the gp70 sequence, and thus meets the further limitation of claim 11. As such, the teachings of Pinter also anticipate claims 10-12.
Claim 17 is directed to an independent claim having the same limitations as claim 1, except that the target antigen of the third step are part of a “panel comprising a solid-phase substrate having said target antigen immobilized thereto”. Pinter further teaches that the serum sample was applied “to a column containing immobilized Case A2 fusion protein” (which is the “target antigen” of Pinter). As such, the teachings of Pinter also anticipate claim 17.
Claims 18, 19 and 23 encompass a method of claim 17 wherein the target antigen is a recombinantly produced and includes at least two (claim 18) or six (claim 19) contiguous histidines or is synthetic (claim 23). These further limitations are also taught by Pinter as set forth above for claims 2 and 3.
Claims 20 and 22 encompass a method of claim 17 wherein the histidine polymers comprise fusions comprising a truncated version of a target antigen protein having at least two contiguous histidines at its C-terminal (claim 20) or that has at least five contiguous histidines (claim 22) These further limitations are also taught by Pinter as set forth above for claim 11.
Claim 21 encompasses a method of claim 20 wherein the anti-poly-histidine antibodies are removed from the serum sample by an affinity purification step by contact with histidine polymers immobilized on a solid substrate. Pinter further teaches that the sample was “absorbed on a column containing p621” (¶ 61) (which comprises His6 and is the “histidine polymer”), which is encompassed by affinity purification using histidine polymers immobilized on a solid substrate.
Claim 25 encompasses a method of claim 17 wherein the sample is obtained from a human subject. This further limitation is also taught by Pinter as forth above for claim 6.
Claim 26 encompasses a method of claim 17 wherein the sample is serum. This further limitation is also taught by Pinter as set forth above for claim 7.
Claim 27 encompasses a method of claim 17 wherein the histidine polymers comprise at least six contiguous histidines. This further limitation is also taught by Pinter as set forth above for claims 8 and 9.
(2) Claims 1-3, 5, 7-9, 17-19, 23 and 26-27 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Mamalaki et al, U.S. Patent Application Publication 20110097749, published 4/28/11, filed 8/2/208 and claiming priority to 8/24/07. The earliest date to which the instant application claims priority is 2/3/21.
Claim 1 encompasses a method of screening a biological sample for antibodies that specifically bind a target antigen by (1) obtaining said sample from a subject; (2) subjecting said sample to histidine polymers to remove anti-poly-histidine antibodies; (3) contacting said target antigen with said sample; and (4) detecting binding of antibodies in said sample to said target antigen.
Mamalaki teaches Hep-25His fusion protein, which consists of a hepicidin-25 (Hep-25) protein with a His tag of six histidines fused to the C-terminus, as shown in SEQ ID NO: 6 (¶ 24). Mamalaki further teaches a method comprising (1) obtaining a biological sample (serum) from an individual (a rabbit immunized with Hep-25His sequence) (¶ 99); (2) subjecting said sample to histidine polymers (6His) to remove anti-poly-histidine antibodies (“In order to remove all anti-His antibodies, the antiserum was subjected to repeated passages from a 6His-coupled sepharose column”; ¶ 99); (3) contacting the Hep-25His peptide with the sample (¶ 99); and (4) detecting binding of antibodies in said sample to the Hep-25His (“The five times purified antiserum recognized specifically H25His peptide”; ¶ 99). As such, the teachings of Mamalaki anticipate claim 1.
Claims 2, 3 and 5 encompass a method of claim 1 wherein the target antigen is a synthetic antigen comprising at least six contiguous histidines (claim 2) and that is a recombinantly produced (claim 3) or produced by a yeast expression system (claim 5). The Hep-25His target antigen of Mamalaki contains 6 contiguous histidines and was recombinantly produced in yeast cells (¶ 93). As such, the teachings of Mamalaki also anticipate claims 2, 3 and 5.
Claim 7 encompasses a method of claim 1 wherein the sample is a serum sample. In the teachings of Mamalaki set forth above, the sample is a serum sample. As such, the teachings of Mamalaki also anticipate claim 7.
Claims 8 and 9 encompass a method of claim 1 wherein the histidine polymers comprise at least six contiguous histidines. In the teachings of Mamalaki set forth above, the histidine polymers are 6His peptide, which comprises 6 contiguous histidines. As such, the teachings of Mamalaki also anticipate claims 8 and 9.
Claim 17 is an independent claim having the same limitations as claim 1, except that the target antigen of the third step is part of a “panel comprising a solid-phase substrate having said target antigen immobilized thereto”. Mamalaki further teaches that the antiserum was subsequently “further purified with Hep-25His-sepharose” (¶ 99), which constitutes the target antigen (Hep-25His) immobilized on a solid-phase substrate (sepharose). As such, the teachings of Mamalaki also anticipate claim 17.
Claims 18, 19 and 23 encompass a method of claim 17 wherein the target antigen is recombinantly produced and includes at least two (claim 18) or six (claim 19) contiguous histidines, or is a synthetic antigen (claim 23). These limitations are met by the teachings of Mamalaki for the same reasons as for claims 2 and 3 set forth above.
Claim 26 encompasses a method of claim 17 wherein the sample is serum. This is met by the teachings of Mamalaki for the same reasons as for claim 7 set forth above.
Claim 27 encompasses a method of claim 17 wherein the histidine polymers comprise at least six contiguous histidines. This limitation is met by the teachings of Mamalaki for the same reasons as for claims 8 and 9 set forth above.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were effectively filed absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned at the time a later invention was effectively filed in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 7 and 31 are rejected under 35 U.S.C. 103(a) as being unpatentable over Mamalaki et al, U.S. Patent Application Publication 20110097749, published 4/28/11. as applied to claims 1 and 17 above, and further in view of Gromme et al, 2011. Proc Natl Acad Sci USA. 96: 10326-10331.
Claims 7 and 31 each limit the method of the respective parent claim (claim 1 or 17) to one wherein the target antigen is a human leukocyte antigen (HLA).
The teachings of Mamalaki that anticipate parent claims 1 and 17 are set forth above. Mamalaki does not further teach that the target antigen is an HLA.
Gromme teaches use of “a rabbit polyclonal anti-MHC class I antibody” for use in staining tissues for the MHC class I molecules (page 10327). MHC class I is a type of HLA. Gromme does not further teach how to make such an antibody.
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to take the method of making a rabbit polyclonal anti-hepcidin antibody taught by Mamalaki and substitute the hepcidin protein with the MHC class I protein as taught by Gromme. The person of ordinary skill in the art would have been motivated to make such a change in order to have a means for production of a rabbit polyclonal anti-MHC class I antibody for use such as taught by Gromme. The person of ordinary skill in the art would have had a reasonable expectation of success in the making such a change because it would only require a simple substitution of one target antigen for another target antigen. This rationale supports a prima facie conclusion of obviousness in accord with KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (2007).
Notes on Patentability
The specification describes the invention as being directed to an improvement to the field of “[i]mmunoassays using protein antigens which specifically bind with specific antibodies” for the purpose of “detecting the presence of such antibodies in biological samples” (page 1). These assays are used for the detection of “antibodies associated with infectious disease pathogens” (page 1) as well as for “determining the compatibility of transplanted organ and tissue by the detection of antibodies to the highly polymorphic Human leukocyte antigen (HLA)” (page 2).
The specification teaches that anti-poly-histidine antibodies may occur in certain subpopulations and create false positive results (page 3). Therefore, the specification teaches that such assay methods can be improved by removing anti-poly-histidine antibodies from the biological sample prior to conducting the assay with the target antigen to detect the presence of the target antibodies (page 4).
During examination of the pending claims no prior art was identified that teaches or suggests removing anti-poly-histidine antibodies from a biological sample prior to performing an immunoassay on the sample with an antigen, or teaches or suggests a method including a step of contacting the sample with poly-histidine polymers to remove anti-poly-histidine antibodies to assay with an antigen. However, the claims as currently recited broadly encompass methods where poly-histidine antibodies are removed from serum samples of animals immunized with histidine-tagged proteins. See the prior art rejections over Mamalaki and Pinter set forth above.
Dependent claim 34 further limits independent parent claim 34 to a method that is carried out on a lateral flow immunoassay device in which a sample fluid flows from a first position to a second position along a test strip and upon which the histidine polymers are immobilized between the first and second positions. This allows the collected sample to pass through the polyhistidine polymers, removing the anti-polyhistidine antibodies prior to assay. Lateral flow immunoassay devices are well known in the relevant prior art; see, for example the review by Koczula et al (2016. Essays in Biochemistry: 60: 111-120). Koczula teaches that these devices “are the technology behind low-cost, simple, rapid and portable detection devices popular” in many fields. Thus, the further limitation of claim 34 limits the claimed method to a device employed by the field of immunoassays and thus is not obvious over the prior art cited above which is directed to generation of antibodies.
Conclusion
Claims 1-3, 5-12, 16-23, 25-27 and 31 are rejected.
Claim 34 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZACHARY C HOWARD whose telephone number is (571)272-2877. The examiner can normally be reached on Monday to Friday from 9 AM to 5 PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Vanessa Ford, can be reached at telephone number (571) 272-0857. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ZACHARY C HOWARD/Primary Examiner, Art Unit 1674
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