DETAILED ACTION
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 .
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 (i.e., changing from AIA to pre-AIA ) 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.
Withdrawn Objections/Rejections
The objections to the specification are withdrawn in response to the amendments.
The objections to the claims are withdrawn in response to the amendments.
The rejection of the claims under 102 are withdrawn in response to the amendments. However, new grounds of rejection are set forth below.
Priority
The present application was filed as a proper National Stage (371) entry of PCT Application No. PCT//EP2020/078174, filed 10/07/2020. Acknowledgment is also made of applicant's claim for foreign priority under 35 U.S.C. 119(a)-(d) to Application No. GB1914517.6, filed on 10/08/2019 in the United Kingdom of Great Britain and Northern Ireland.
Status of the Claims
Claims 1-7, 9 and 12-16 are pending; claims 1-7, 9, 13-14 and 16 are amended, claims 8, 10-11 and 17-18 are canceled; claims 12-16 are withdrawn. Claims 1-7 and 9 are examined below.
Maintained Rejections
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-7 and 9 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 and its dependent claims require an antibody that specifically binds to XBP1s and a second antibody that specifically binds to XBP1u. Dependent claim 2 requires that the antibody specific to XBP1u binds to an epitope incorporated within SEQ ID NO: 3 of XBP1u and the antibody specific to XBP1s binds to an epitope incorporated within SEQ ID NO: 4 of XBP1s. Dependent claim 6 requires a detector antibody specific to an epitope present in both XBP1u and XBP1s. Dependent claim 7 requires the detector antibody being specific to an epitope present within SEQ ID NO: 5.
The specification does not describe which amino acid residues, nucleic acid residues, or other molecular components are present in the genus of agents encompassed by claims 1-7 and 9. The specification fails to disclose the structures common to all members of the genus and fails to provide sufficient specific examples of agents to be used. In the absence of a known or disclosed correlation between structure and function, claims which encompass variants defined by their function are generally not considered described. Applicant is directed to MPEP § 2163 for guidelines on compliance with the written description requirement.
Regarding the claimed scope that includes antibodies, the Federal Circuit has clarified Written Description as it applies to antibodies in the recent decision Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017). The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. 112(a) (or pre-AIA first paragraph) requires adequate written description of the antibody itself. Amgen, 872 F.3d at 1378-79. The Amgen court expressly stated that the so-called “newly characterized antigen” test, which had been based on an example in USPTO-issued training materials and was noted in dicta in several earlier Federal Circuit decisions, should not be used in determining whether there is adequate written description under 35 U.S.C. 112(a) for a claim drawn to an antibody. Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the “newly characterized antigen” test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad, 598 F.3d 1336, 1345 (Fed. Cir. 2010). In view of the Amgen decision, adequate written description of an antigen alone is not considered adequate written description of a claimed antibody to that antigen, even when preparation of such an antibody is routine and conventional. Id.
While generically the structure of antibodies is known, the structure of the presently recited antibodies can vary substantially within the above given claimed recitations. As noted in Amgen, knowledge that an antibody binds to a particular epitope on an antigen tells one nothing at all about the structure of the antibody, wherein “instead of analogizing the antibody-antigen relationship to a ‘key in a lock,’ it [is] more apt to analogize it to a lock and ‘a ring with a million keys on it.” (Internal citations omitted). The relevant antibody art confirms this quandary, indicating that “knowledge of an epitope or antigen used to generate a monoclonal antibody is insufficient for making the original antibody available, even if suitable in vitro test systems for screening are used.” See p. 8, lines 3-5 of WO 2009/033743 A1. Therefore, those of skill in the art would not accept that the inventor had been in possession of the full genus of antibodies and variants, fragments or derivates of the antibodies of the claims.
Functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. Abbvie Deutschland GMBH & Co. v. Janssen Biotech, Inc. (759 F.3d 1285 (Fed. Cir. 2014). “When a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus." Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005).
In this case, the specification fails to disclose any example of an antibody specific for XBP1u, XBP1s or XBP1u and XBP1s. Although the specification page 16 discloses that “[m]embranes were probed with commercial antibodies to spliced and unspliced XBP1 isoforms and Actin (Sigma-Aldrich, St. Louis, USA, 1l5000)”, no specific product number of the antibody is disclosed. Consequently, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the full genus of antibodies encompassed by the claims. Further, given the well-known high level of polymorphism of immunoglobulins and antibodies, the skilled artisan would not have recognized that applicant was in possession of the vast repertoire of encompassed antibodies.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111 (Fed. Cir. 1991), clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117). The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
The skilled artisan cannot envision the detailed chemical structure of each genus of claimed agents, i.e., one antibody specific to XBP1u the second antibody specific to XBP1s (claims 1-2) and the detector antibody specific to an epitope present in both XBP1u and XBP1s (claims 6-7). Conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of identification. Adequate written description requires more than a mere statement that it is part of the invention. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991). Therefore, the instant claims do not meet the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph.
New Rejection
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.
Claim 4 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 4, the phrase "such as" in line 6 renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Therefore the claim is rejected under 112b.
Maintained Rejections
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 4 is rejected under 35 U.S.C. 101 because the claimed invention is directed to at least one judicial exception without significantly more.
The U.S. Patent and Trademark Office recently revised the MPEP with regard to § 101 (see the MPEP at 2106). Regarding the MPEP at 2106, in determining what concept the claim is “directed to,” we first look to whether the claim recites:
(1) any judicial exceptions, including certain groupings of abstract ideas (i.e., mathematical concepts, certain methods of organizing human activity such as a fundamental economic practice, or mental processes); and
(2) additional elements that integrate the judicial exception into a practical application (see MPEP § 2106.05(a)-(c), (e)-(h)).
Only if a claim (1) recites a judicial exception and (2) does not integrate that exception into a practical application, do we then look to whether the claim contains an “‘inventive concept’ sufficient to ‘transform’” the claimed judicial exception into a patent-eligible application of the judicial exception. Alice, 573 U.S. at 221 (quoting Mayo, 566 U.S. at 82). In so doing, we thus consider whether the claim:
(3) adds a specific limitation beyond the judicial exception that is not “well-understood, routine, conventional” in the field (see MPEP § 2106.05(d)); or
(4) simply appends well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception.
See MPEP 2106.
ELIGIBILITY STEP 2A: WHETHER A CLAIM IS DIRECTED TO A JUDICIAL EXCEPTION
Step 2A, Prong 1
Prong One asks does the claim recite an abstract idea, law of nature, or natural phenomenon? In Prong One examiners evaluate whether the claim recites a judicial exception, i.e. whether a law of nature, natural phenomenon, or abstract idea is set forth or described in the claim. While the terms "set forth" and "described" are thus both equated with "recite", their different language is intended to indicate that there are two ways in which an exception can be recited in a claim. For instance, the claims in Diehr, 450 U.S. at 178 n. 2, 179 n.5, 191-92, 209 USPQ at 4-5 (1981), clearly stated a mathematical equation in the repetitively calculating step, and the claims in Mayo, 566 U.S. 66, 75-77, 101 USPQ2d 1961, 1967-68 (2012), clearly stated laws of nature in the wherein clause, such that the claims "set forth" an identifiable judicial exception. Alternatively, the claims in Alice Corp., 573 U.S. at 218, 110 USPQ2d at 1982, described the concept of intermediated settlement without ever explicitly using the words "intermediated" or "settlement." See MPEP 2106.04 (II)(A)(1).
Claim 4 recites “[t]he method of claim 1, wherein the amount of XBP1u and XBP1s is determined by comparison with a calibrator curve or following their determination an XBP1s and XBP1u ratio is derived…”.
The “comparison” of claim 4 may be categorized as an abstract idea, namely mental processes/concepts performed in the human mind (such as simply thinking about the measured amount of XBP1u and XBP1s in relation to a calibration value and making an evaluation, judgment, or opinion). The claims, under their broadest reasonable interpretation, cover performance of determining the amount of XBP1u and XBP1s solely within the human mind, or by a human using pen and paper. Comparing information regarding a sample to a control or target data (in this case, comparing a numerical amount to a calibration curve) represents abstract ideas.
The “ratio” of claim 4 may also be categorized as an abstract idea, namely a mathematical calculation.
Claim 4 further recites “and wherein based upon the detection or determination of the amount of XBP1s and XBP1u, the unfolded protein response status of the in vitro cell line or in vitro biological sample taken from the individual is ascertained such as to stratify the individual for targeted therapies and/or monitor efficacy of a drug to which the individual or cell line has been exposed”.
Thus, claim 4 also describes a natural correlation. The natural relationship to which claim 4 is directed (i.e., the relation between the amount of XBP1u and XBP1s, and unfolded protein response status, as well as the relation between the amount of XBP1u and XBP1s and drug efficacy and therapeutic specificity (stratify the individual for targeted therapy)) is a law of nature. Similar concepts have been held by the courts to constitute law of nature/natural phenomena, as in the identification of a correlation between the presence of myeloperoxidase in a bodily sample (such as blood or plasma) and cardiovascular disease risk in Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1361, 123 USPQ2d 1081, 1087 (Fed. Cir. 2017). In Mayo, the Supreme Court found that a claim was directed to a natural law, where the claim required administering a drug and determining the levels of a metabolite following administration, where the level of metabolite was indicative of a need to increase or decrease the dosage of the drug. See Mayo Collaborative Services v. Prometheus Labs., Inc., 566 U.S. 66, 74 (2012).
The instant claims are similar to those in Mayo as they involve a "relation itself [which] exists in principle apart from any human action" (id. at 77), namely the relationship between the naturally occurring amount of XBP1u and XBP1s in an in vitro biological sample taken from an individual and the status of unfolded protein response, drug efficacy and targeted therapy.
The correlation between XBP1u and XBP1s and disease or therapeutic efficacy/specificity is a judicial exception as it exists in principle apart from any human action; the correlation itself therefore cannot form the basis for eligibility.
Step 2A, Prong 2
The claim also recites “bringing an in vitro cell line or an in vitro biological sample taken from an individual into contact with a solid-state device supporting two antibodies at discrete locations on the solid-state device, a first antibody specific to XBP1u, and a second antibody specific to XBP1s; adding at least one further detector antibody; and detecting or determining the amount of XBP1u and XBP1s, and wherein the solid-state device is a biochip” (claim 1). Such steps of providing a sample and measuring the amount of XBP1u and XBP1s therein using an antibody are insufficient to integrate the judicial exception(s) because the purpose is merely to obtain data. This does not go beyond insignificant presolution activity, i.e., a mere data gathering step necessary to use the correlation, similar to the fact pattern in In re Grams, 888 F.2d 835 (Fed. Cir. 1989) and Ariosa Diagnostics, Inc. v. Sequenom, Inc. (Fed. Cir. 2015). Furthermore, the steps of determining the amount of XBP1u and XBP1s are recited at a high level of generality and are not tied, for example, to any particular machine or apparatus.
Furthermore, “to stratify the individual for targeted therapies and/or monitor efficacy of a drug to which the individual or cell line has been exposed” fails to integrate the judicial exception(s) into a practical application. These limitations are considered insignificant extra-solution activities that fail to use, rely on, or apply the judicial exception(s) such to amount to a practical application thereof.
ELIGIBILITY STEP 2B: WHETHER THE ADDITIONAL ELEMENTS CONTRIBUTE AN "INVENTIVE CONCEPT"
The additional elements of the claims, including the steps of bringing an in vitro cell line or an in vitro biological sample from an individual and detecting or determining the amount of XBP1u and XBP1s therein, do not add significantly more to the judicial exception(s). The step of detecting or determining the amount of XBP1u and XBP1s is recited at a high level of generality and is not limited, for example, to any specific testing technique.
Although measurement of XBP1u and XBP1s is performed using an antibody that specifically binds to XBP1u and XBP1s, no particular or specific antibody is set forth.
In this case, there is evidence that it was well-understood, routine and conventional to determine the amount of XBP1u and XBP1s in samples using antibodies specific for XBP1u and XBP1s.
See for example, Glimcher et al. (WO 2010/008860 A1) (“Glimcher”) teaches that “[t]he techniques for assessing the ratios of unspliced to spliced XBP-1 and spliced to unspliced XBP-1 are routine in the art…[b]ecause the spliced form of XBP-1 comprises an exon not found in the unspliced form, in another embodiment, antibodies that specifically recognize the spliced or unspliced form of XBP-1 can be developed using techniques well known in the art (Yoshida et al. 2001. 25 Cell. 107:881)… The ratio of the different forms of XBP-1 can be determined using these or other art recognized methods” (page 50 lines 27-33 and page 51 lines 1-2).
Urano (WO 2005034737 A2) (Cite No. 1 of IDS 3/30/2022) teaches that “levels of ER stress are detected using a binding agent specific for the spliced or unspliced form of XBP-1 protein. In some embodiments, the binding agent is an antibody that is specific for the spliced or unspliced form” (page 16 lines 1-3).
Guo et al. Cellular Signaling 22 (2010) 1818–1828 (Cite No. 1 of IDS 3/30/2022) (“Guo”) teaches that “XBP1U and XBP1S proteins were detected using anti-XBP1U (Novus Biologicals) and anti-XBP1S antibody (Biolegend)” (page 1820 col. 2 para. 2).
Furthermore, using at least one further detector antibody is well-understood, routine and conventional. Glimcher teaches that “[t]echniques for detecting antibody binding are well known in the art… antibody binding is detected through the use of a secondary antibody that is conjugated to a labeled polymer” (page 87 lines 34-35 and page 88 lines 1-2). Also, Urano teaches that “[t]he antibodies can be labeled to facilitate detection and quantification of XBP-1 splicing…a labeled secondary antibody is used” (page 17 lines 22-23 and 27).
In view of the above evidence, the claimed steps of determining the amount of XBP1u and XBP1s using antibodies do not add any feature that is more than well-understood, purely conventional, or routine in the field of diagnostics and biochemical assay methodologies.
When recited at this high level of generality, there is no meaningful limitation, such as a particular or unconventional machine or a transformation of a particular article, in this step that distinguishes it from well-understood, routine, and conventional data gathering activity engaged in by scientists prior to applicant’s invention, and at the time the application was filed, e.g., the routine and conventional techniques of detecting a protein using an antibody to that protein. See also MPEP 2106.05(g). Although the claims recite “a solid-state device supporting two antibodies at discrete locations on the solid-state device, one antibody specific to XBP1u the second specific to XBP1s”. There is evidence that this technique is also well-understood, routine and conventional.
For example, Glimcher further teaches that “antibodies which are reactive with protein or target molecules but which do not interfere with binding of the protein to its target molecule can be derivatized to the wells of the plate, and unbound target or XBP-1. protein is trapped in the wells by antibody conjugation. Methods for detecting such complexes… include immunodetection of complexes using antibodies reactive with XBP-1…as well as enzyme-linked assays which rely on detecting an enzymatic activity associated with the XBP-1” (page 60 lines 10-18).
McAleer et al. Journal of Immunoassay & Immunochemistry, 27: 363–378, 2006 (Cited on PTO-892 5/21/2025) (“McAleer”) teaches that “[i]n the late 1980s, the concept of assays based on ligand binding on microarrays was introduced by Ekins et al.[1 – 3] Panels of microarrays can increase the capacity of detection and quantification of biomarkers, as analysis of several biomarkers can be performed at the same time with a single patient sample. The development of stable, reproducible protein-biochip microarray technology and the automation of biochip-based immunoassays in a fully automated high-throughput Evidence system have been reported.[4] This technology uses a chemically activated biochip (9 mm2) as solid support, in which multiple specific protein ligands are precisely dispensed, immobilized, and stabilized in predefined x, y coordinates, creating ordered discrete test regions (DTRs) forming arrays. The biochip is then used as the reaction platform to perform competitive or sandwich immunoassays” (page 363 and page 364 para. 1).
Furthermore, there is evidence that using a biochip as a solid state device is well-understood, routine and conventional.
For example, Sha et al. Chin J Anal Chem, 2013, 41(2), 199–204 DOI: 10.1016/S1872-2040(13)60627-1 (“Sha”) teaches that “Immunochip, also named antibody chip, is the most common type of protein chips for research and application. The principle of immuonochip construction is to immobilize several to tens of thousands, or even more antibodies onto a solid substrate as capture layers. Multiple target molecules in a sample are detected on the chip through antibody-antigen specific interaction and followed by detection techniques to obtain multiple parameters[1]” (page 1 col. 1 para. 1).
Also, Welch et al. Biointerphases 12, 02D301 (2017) https://doi.org/10.1116/1.4978435 (“Welch”) teaches that “Immunodiagnostics, protein biochips, and biosensors employed for antigen detection and quantification from biological samples often employ recognition proteins such as antibodies” (page 1 col. 1 para. 1).
Also, there is evidence that stratifying the individual for targeted therapies and/or monitoring the efficacy of a drug to which the individual or cell line has been exposed is well-understood routine and conventional.
For example, Fotheringham et al. (JP 2009531051 A) (“Fotheringham”) teaches “a screening method that allows the identification of disease biomarkers. The types of biomarkers that can be identified predict the susceptibility of a disease to new or existing drugs, thereby allowing patients to be stratified into groups that are more likely to respond and groups that are more likely not to respond” (para. 5). Fotheringham further teaches “monitoring therapeutic treatment of a disease or physiological condition in a patient” (para. 59).
Also, Clark et al. (KR 20130095183 A) (“Clark”) teaches “predicting drug responses and monitoring disease states” (para. 1). Clark further teaches that “[o]verall, in vitro biomarkers provide the possibility of a functional assay systematically querying the entire signaling network. These assays provide several possible applications, including new pharmacokinetic assays for use in the development of target therapies and patient stratification based on functional information to determine clinical management or clinical trial designs (Clark DP. Ex vivo biomarkers: functional tools to guide targeted drug development and therapy. Expert Rev Mol Diagn2009; 9 (8): 787-94)” (para. 7). Clark further teaches that “[a]lso provided are methods and compositions for… monitoring the therapeutic efficacy of the therapeutic method” (para. 9).
For all of these reasons, the claims fail to include additional elements that are sufficient to amount to significantly more than the judicial exception(s).
New Rejections
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 1, 3-6 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Glimcher (WO 2010008860)-(Cite No. O of PTO 892 9/4/2025) in view of McAleer et al. Journal of Immunoassay & Immunochemistry, 27: 363–378, 2006 (Cited on PTO-892 5/21/2025) (“McAleer”) as evidenced by Randox, Biochip Array Technology (retrieved online https://randoxfood.com/biochip/ on 8/29/2025) -(Cite No. U of PTO 892 9/4/2025).
Regarding claims 1, 3, 5 and 9, Glimcher teaches a method of detecting or determining amount of the proteins XBP1u and XBP1s (“the invention provides for screening assays to identify compounds which alter the ratio of spliced XBP-1 to unspliced XBP-1 or the ratio of unspliced XBP-1 to spliced XBP-1” page 53 lines 30-32, “The techniques for assessing the ratios of unspliced to spliced XBP-1 and spliced to unspliced XBP-1 are routine in the art…. Because the spliced form of XBP-1 comprises an exon not found in the unspliced form, in another embodiment, antibodies that specifically recognize the spliced or unspliced form of XBP-1 can be developed using techniques well known in the art (Yoshida et al. 2001. 25 Cell. 107:881)… The ratio of the different forms of XBP-1 can be determined using these or other art recognized methods” page 54 lines 19-25 and 31-32), comprising bringing an in vitro cell line or an in vitro biological sample taken from an individual (“A. Cell Based Assays The indicator compositions of the invention can be a cell that expresses an XBP-1, … for example, a cell that naturally expresses endogenous XBP-1 or, more preferably, a cell that has been engineered to express an exogenous XBP-1 protein by introducing into the cell an expression vector encoding the protein” page 40 lines 12-17, “Cell-free assays…Alternatively, a lysate or an extract of cells expressing the protein of interest can be prepared for use as cell-free composition” page 57 line 31 and page 58 lines 1-2) into contact with a solid-state device supporting two antibodies at discrete locations on the solid-state device, one antibody specific to XBP1u and a second antibody specific to XBP1s (“[o]ther techniques for immobilizing proteins on matrices can also be used in the screening assays of the invention…antibodies which are reactive with protein or target molecules but which do not interfere with binding of the protein to its target molecule can be derivatized to the wells of the plate, and unbound target or XBP-1. protein is trapped in the wells by antibody conjugation” page 60 lines 3-4 and 10-13) adding at least one further detector antibody, and detecting or determining the amount of XBP1u and XBP1s (“Methods for detecting such complexes…include immunodetection of complexes using antibodies reactive with XBP-1” page 60 lines 13-18). Note that although Glimcher does not use the language “at discrete locations on the solid-state device”, given that Glimcher teaches that “antibodies …can be derivatized to the wells of the plate”, this inherently provides a step of the antibodies being supported by the solid-state deice at discrete locations. Also, although Glimcher fails to use the language “one antibody specific to XBP1u and a second antibody specific to XBP1s” with regards to them being supported by the solid-state device, the teaching of “XBP-1. protein is trapped in the wells by antibody conjugation” inherently provides the step of the solid-state device supporting one antibody specific to XBP1u the second antibody specific to XBP1s because Glimcher teaches that “[u]nless the form is referred to explicitly herein, the term "XBP-1" as used herein includes both the spliced and unspliced forms” (page 27 lines 6-7). Also, the antibody specific to XBP1u, the second antibody specific to XBP1s and the solid-state device are all taught under the embodiment “Screening Assays” (page 37 line 28). Glimcher does teach the solid-state device under the subsection “C. Cell-free assays” (page 57 line 31), however, the umbrella section “Screening Assays” also teaches that “the invention pertains to a combination of two or more of the assays described herein. For example, a modulating agent can be identified using a cell-based or a cell-free assay” (page 39 lines 24-26). Furthermore, the cell-free assays also include “a lysate or an extract of cells expressing the protein of interest” (page 58 lines 1-2). Note that the specification teaches the use of cell lysates as in vitro cell-line samples to be used in the Examples disclosed (“Sample preparation Cells were washed once in ice cold phosphate buffered saline (PBS) and then lysed in either RIPA buffer” page 16 para. 2). Therefore, Glimcher does teach a method of detecting or determining the amount of XBP1u and XBP1s, the method comprising bringing an in vitro cell line or an in vitro biological sample taken from an individual into contact with a solid-state device supporting two antibodies at discrete locations on the solid-state device, a first antibody specific to XBP1u and a second antibody specific to XBP1s; adding at least one further detector antibody; and detecting or determining the amount of XBP1u and XBP1s in a single embodiment, i.e. drawn to the “screening assays”.
Glimcher fails to teach wherein the first antibody specific to XBP1u and the second antibody specific to XBP1s are simultaneously exposed to the in vitro cell line or in vitro biological sample and the XBP1u and the XBP1s proteins are detected or determined simultaneously, wherein the solid-state device has a chemically reactive surface to which the two antibodies are bonded, wherein the solid-state device is a biochip, wherein the biochip is ceramic.
McAleer teaches “[t]he semiautomated Evidence Investigator” (Abstract). McAleer suggests wherein the first antibody specific to XBP1u and the second antibody specific to XBP1s are simultaneously exposed to the in vitro cell line or in vitro biological sample and the XBP1u and the XBP1s proteins are detected or determined simultaneously, wherein the solid-state device has a chemically reactive surface to which the two antibodies are bonded, wherein the solid-state device is a biochip, wherein the biochip is ceramic (“stable, reproducible protein-biochip microarray technology and the automation of biochip-based immunoassays in a fully automated high-throughput Evidence system have been reported.[4] This technology uses a chemically activated biochip (9 mm2) as solid support, in which multiple specific protein ligands are precisely dispensed, immobilized, and stabilized in predefined x, y coordinates, creating ordered discrete test regions (DTRs) forming arrays. The biochip is then used as the reaction platform to perform competitive or sandwich immunoassays. Nine biochips are held in a carrier and are automatically processed during the immunoassay steps. The supercooled charged couple device (CCD) camera in the analyser simultaneously detects the light signals emitted by the DTRs of the array and the dedicated software processes, quantifies, validates, and archives the multiple data… The use of biochip array platforms offers benefits in sample analysis, enabling assay miniaturization, and simultaneous measurement of multiple analytes using reduced sample and reagent volumes. Furthermore, they facilitate more cost-effective and comprehensive approaches to the study of pathological conditions. This technology paves the way to the development of flexible ranges of biochip-array multiplexed assays” page 364 para. 1, “the activated solid substrate of 9 mm2 containing immobilized antibodies specific to the adhesion molecules, in defined discrete test regions (DTRs), in an ordered array arrangement. The biochips were supplied in individually labelled carriers containing 3x3 biochips, which is equivalent to 9 reaction wells per carrier, where samples and reagents were added to perform the assay” page 366 para. 5). Note that the Evidence Investigator taught by McAleer is the same solid-state device disclosed in the instant specification page 15 paragraph 2 (“XBP1s and XBP1u levels and raw signal were quantified using the Evidence Investigator analyser (EV3602, Randox Laboratories Ltd., UK)”). Also note that the Evidence Investigator uses a ceramic biochip as evidenced by Randox (“What is Biochip Technology?... a 9mm x 9mm ceramic chip” page 1 para. 2, “Evidence Investigator…Using biochip technology” page 2 para. 2).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Glimcher to rely on the solid state device wherein the first antibody specific to XBP1u and the second antibody specific to XBP1s are simultaneously exposed to the in vitro cell line or in vitro biological sample and the XBP1u and the XBP1s proteins are detected or determined simultaneously, wherein the solid-state device has a chemically reactive surface to which the two antibodies are bonded, wherein the solid-state device is a biochip, wherein the biochip is ceramic suggested by McAleer because McAleer suggests that this biochip array platforms offers benefits in sample analysis, enabling assay miniaturization, reduced sample and reagent volumes, and more cost-effective and comprehensive approaches to the study of pathological conditions. A person having ordinary skill in the art would have had a reasonable expectation of success because both Glimcher and McAleer teach a solid-state device supporting two antibodies at discrete locations for immunoassay applications.
Regarding claim 4, Glimcher in view of McAleer teach the method of claim 1 as discussed above.
Glimcher further suggests following their determination an XBP1s and XBP1 u ratio is derived (page 53 lines 30-32, page 54 lines 19-25 and 31-32). Although Glimcher fails to use the language “ratio is derived”, the teaching of screening assays that alter the ratio together with the teachings of techniques for assessing the ratio, inherently provides a step of deriving the ratio. Glimcher further teaches wherein based upon the detection or determination of XBP1s and XBP1u the unfolded protein response status of the cell line or biological sample taken from the individual is ascertained (“XBP-1 has also been shown to be a key factor … to enhance the compensatory [unfolded protein response] UPR” page 26 lines 28-30, “biological activities of XBP-1 described herein include… modulation of the UPR” page 41 lines 11 and 15, “Compounds that alter the ratio of unspliced to spliced XBP-1 or spliced to unspliced XBP-1 can be useful to modulate the biological activities of XBP-1, e.g., in modulation of the UPR” page 54 lines 11-13). Although Glimcher fails to use the language “wherein based upon the detection or determination of XBP1s and XBP1u the unfolded protein response status of the cell line or biological sample taken from the individual is ascertained”, the teaching of screening assays for compounds that alter the ratio of XBP1s and XBP1u together with the teaching that XBP1s and XBP1u enhance and modulate the UPR, inherently provides in which based upon the detection or determination of XBP1s and XBP1u the unfolded protein response status of the cell line or biological sample taken from the individual is ascertained. Glimcher further suggests such as to stratify the individual for targeted therapies (“These findings provide for methods to identify agents that modulate, e.g., decrease, the expression and/or activity of XBP-1… In addition, the invention provides for the use of agents that modulate the expression and/or activity of XBP-1…as targets in therapy” page 19 lines 14-17). Note that although Glimcher fails to use the language “stratify the individual”, the teaching of using the agents that modulate the expression of XBP-1 as targets in therapy inherently provides the stratification of the individual receiving the therapy because the process of identifying agents that modulate XBP1 would inherently stratify the individual.
Regarding claim 6, Glimcher in view of McAleer teach the method of claim 1 as discussed above.
Glimcher further teaches wherein the detector antibody is specific to an epitope present in both XBP1u and XBP1s (page 60 lines 13-18). Note that although Glimcher fails to use the language “detector antibody is specific to an epitope present in both XBP1u and XBP1s”, the teaching of “immunodetection of complexes using antibodies reactive with XBP-1” together with “[u]nless the form is referred to explicitly herein, the term "XBP-1" as used herein includes both the spliced and unspliced forms” (page 27 lines 6-7) inherently provides in which the detector antibody is specific to an epitope present in both XBP1u and XBP1s.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Glimcher in view of McAleer as applied to claim 1 above, and further in view of Urano (WO 2005034737 A2) (Cite No. 1 of IDS 3/30/2022) (“Urano”).
Regarding claim 2, Glimcher in view of McAleer teach the method of claim 1 as discussed above.
Glimcher in view of McAleer fail to teach wherein the antibody specific to XBP1u binds to an epitope incorporated within SEQ ID NO: 3 of XBP1u and the antibody specific to XBP1s binds to an epitope incorporated within SE QID NO: 4 of XBP1s.
Urano teaches “methods and reagents to quantify endoplasmic reticulum stress (ER stress) levels” (Abstract), “the invention provides methods of diagnosing an ER stress disorder,
e.g., diabetes or Wolfram Syndrome, in a subject by quantifying the level of ER stress in a cell or biological sample isolated from the subject according to one of the methods described herein” (page 4 lines 9-12). Urano further teaches that “levels of ER stress are detected using a binding agent specific for the spliced or unspliced form of XBP-1 protein. In some embodiments, the binding agent is an antibody that is specific for the spliced or unspliced form, e.g., recognizes an epitope that is 3' of the splice site. For example, an antibody that is specific for the spliced form can recognize an epitope in SEQ ID NO:6; an antibody specific for the unspliced form can recognize an epitope in SEQ ID NO:7.” (page 16 lines 1-3). Urano further teaches that the “amino acid sequences for the spliced and unspliced forms of XBP-1 are shown in Figures 5… B and 6… B… The bold, underlined regions of the amino acid sequence in Figure 5B is the sequence of the protein encoded by the spliced form that differs from that encoded by the unspliced form, which is bold and underlined in Figure 6B” (page 15 lines 10-12 and 17-19). Note that SEQ ID NO: 7 and SEQ ID NO: 6 of Urano are 100% matched to SEQ ID NO: 3 and SEQ ID NO: 4 of the instant claim, respectively. Urano further teaches that “to facilitate detection… a labeled secondary antibody is used” (page 17 lines 22 and 27).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Glimcher in view of McAleer to rely on in which the antibody specific to XBP1u binds to an epitope incorporated within SEQ ID NO: 3 of XBP1u and the antibody specific to XBP1s binds to an epitope incorporated within SEQ ID NO: 4 of XBP1s taught by Urano because Urano teaches that this enables the quantification of ER stress which enables the diagnosis of ER stress disorders such as diabetes and Wolfram Syndrome. A person having ordinary skill in the art would have had a reasonable expectation of success because both Glimcher in view of McAleer and Urano teach methods of detecting or determining the amount of XBP1u and XBP1s using one antibody specific to XBP1u the second antibody specific to XBP1 and at least one further detector antibody.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Glimcher in view of McAleer as applied to claim 1 above, and further in view of Kaufman (WO 03089622 A2) -(Cite No. P of PTO 892 9/4/2025).
Regarding claim 7, Glimcher in view of McAleer teaches the method of claim 1 as discussed above.
Glimcher in view of McAleer fail to teach wherein the detector antibody is specific to an epitope present within SEQ ID NO: 5.
Kaufman teaches “methods and compositions for modulating the unfolded protein response. The method further relates to methods and compositions for the treatment and diagnosis of protein conformational diseases or disorders” (Abstract). Kaufman further teaches that “[p]rotein conformational diseases or disorders, such as al-antitrypsin deficiency and cystic fibrosis, are associated with the accumulation of unfolded proteins in the endoplasmic reticulum (also referred to as "ER") (Arider et al., 1999; Kaufinan, 1999; Kopito et al., 2000)” (page 1 lines 10-13). Kaufman further teaches “a polypeptide including the amino acid sequence set forth as SEQ ID NO:2… the invention features antibodies (e.g., antibodies which specifically bind to any one of the polypeptides described herein)” (page 3 lines 24-25 and 31-32). Kaufman further teaches that “[t]he present invention further features methods for detecting XBP1 polypeptides, such methods featuring…antibody described herein” (page 4 lines 1-3). Note that SEQ ID NO: 2 is 100% matched to SEQ ID NO: 5 claimed. Also, note that the claim recites open language “comprising”, therefore, even though SEQ ID NO: 2 of Kaufman includes additional amino acids than SEQ ID NO: 5 claimed, the teaching of Kaufman still addresses the claim. Kaufman further teaches an “antibody reactive to the amino-terminus of XBPl” (page 79 lines 9-10).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Glimcher in view of McAleer to rely on the detector antibody being specific to an epitope present within taught by Kaufman because Kaufman suggests this enables the diagnosis of cystic fibrosis. A person having ordinary skill in the art would have had a reasonable expectation of success because both Glimcher in view of McAleer and Kaufman teach methods drawn to the modulation of the unfolded protein response involving XBP1.
Response to Arguments
Applicant's arguments filed 12/4/2025 have been fully considered but they are not persuasive.
Regarding the 112a written description rejections, Applicant argues that “at page 16 of the specification, the Applicant provides information to one of skill in the art where to purchase the antibodies used in the methods and biochips of the disclosure” (page 7 para. 1). However, the disclosure on page 16 provides very generalized information (“[m]embranes were probed with commercial antibodies to spliced and unspliced XBP1 isoforms and Actin (Sigma-Aldrich, St. Louis, USA, 1l5000)”) which is not considered sufficient written description support for the genus of antibodies encompassed by the claim. Furthermore, contrary to Applicant’s remark, the disclosure on page 16 is not drawn to antibodies to be used with the biochips claimed. The specification on page 16 merely discloses the company (“Sigma-Aldrich”) that sells “antibodies to spliced and unspliced XBP1 isoforms” for the immunoblotting experiment (“Immunoblotting…Membranes were probed with commercial antibodies”). Therefore, a person having ordinary skill in the art would not recognize that Applicant was in possession of the genus of antibodies claimed by function “specific to XBP1u…specific to XBP1s” for use in the biochip claimed. Applicant further argues that “Applicant is not claiming the antibodies per se, but rather describing a methods and compositions that use the antibodies” (page 7 para. 1). However, given that the claims require the antibodies specific to XBP1u and XBP1s, the specification must also disclose adequate written description of the antibodies (see rejection above). Applicant further argues that “Applicant submits that one of skill in the art would recognize that Applicant had possession of the claimed invention based upon the public availability of the antibodies. Furthermore, sources of XBP1 antibodies are commercially available from Creative Bio Labs, Sigma among others” (page 7 para. 2). However, although the antibodies may be commercially available, the specification must provide evidence, i.e. disclosure, that Applicant was in possession of the genus of antibodies claimed by function. Otherwise, a person having ordinary skill in the art would doubt that Applicant was indeed in possession of the genus of antibodies claimed. Applicant further argues that “Applicant respectfully submits that the claimed
invention has been reduced to practice…Applicant is not claiming the antibody and thus reliance
on Amgen is misplaced” (page 7 paras. 3-4). However, these arguments are not persuasive given that the specification fails to disclose adequate written description of the antibodies claimed by function. The claims remain rejected under 112a.
Regarding the 101 rejection, Applicant argues that “Claim 4 has been amended to recite that the amount of the isoforms is used to ascertain the UPR status and thus stratify or monitor the patient” (page 8 para. 2). However, using the amount of isoforms to ascertain the UPR status is a natural correlation (see rejection above). Furthermore, “to stratify the individual for targeted therapies and/or monitor efficacy of a drug to which the individual or cell line has been exposed” fails to integrate the judicial exception(s) and fail to add significantly more than the judicial exception(s) (see rejection above). Therefore, claim 4 remains rejected under 101.
Regarding the prior art rejections, Applicant argues that “Applicant notes that the Examiner asserts that a solid-state device is inherently taught by Glimcher since it discloses a cell-free assay including a cell lysate comprising the protein of interest. However, a solid-state device is not at all inherent in Glimcher as there are numerous methods for measuring the amount of an analyte in a cell-free manner other than solid-state devices” (page 8 para. 5). However, contrary to Applicant remark, Glimcher explicitly teaches a solid-state device in page 60 lines 3-4 and 10-13 (see rejection above). Applicant further argues that “Glimcher does not disclose methods involving a biochip” (page 8 para. 5). However, new grounds of rejection are set forth above in response to the amendments. McAleer is relied upon for the teachings of the biochip (see rejection above). Applicant further argues that “[t]he Examiner equates derivatizing the antibodies to the plate" with disclosing two antibodies at discrete locations (see page 60, lines 10-13 of Glimcher). However, this passage states that antibodies for XBP1 or a target
protein can be immobilised to assess the interaction. Derivatizing antibodies means that the antibodies are chemically modified so as to form a stable bond with the surface of the plate, not that there are XBP1s and XBP1u antibodies at separate locations” (page 8 last paragraph and page 9 para. 1). However, the teaching of chemically modifying the antibodies so as to form a stable bond with the surface of the plate inherently provides the antibodies forming a bond with the plate at separate locations. Note that it is not possible to bond two antibodies in the same location because one antibody would obstruct the other from being bonded in that same location. Applicant further argues that “Moreover, this passage refers to the interaction between XBP1 and its target so as to detect or isolate XBP1-target complexes, not to determine the amounts of the two XBP1 isoforms” (page 9 para. 1). However, contrary to Applicant’s argument, the passage of Glimcher does suggest the detecting of XBP1 isoforms because an antibody is being used to trap XBP1 in the wells of the plate (see rejection above). Applicant further argues that “[t]he 'screening assays' in Glimcher (page 53) focus on compounds which alter the ratio of spliced to
unspliced mRNA (see page 53-54) in order to modulate the biological activities of XBP1. Notably, these screening assays fall under the heading "A. Cell Based Assays" in Glimcher (page 40). No such assays are described under the cell-free assay subheading (see page 57), and, even if this were to be the case, there are still numerous cell-free assays which could be employed and no hint whatsoever to sandwich multianalyte immunoassay array biochip” (page 9 para. 5). However, contrary to Applicant’s remark, both the “A. Cell Based Assays” and the “cell-free assay” of Glimcher are taught within the “Screening Assays” section (see page 37 of Glimcher). As stated in the rejection above, the umbrella section “Screening Assays” also teaches that “the invention pertains to a combination of two or more of the assays described herein. For example, a modulating agent can be identified using a cell-based or a cell-free assay” (page 39 lines 24-26 of Glimcher). Furthermore, the cell-free assays also include “a lysate or an extract of cells expressing the protein of interest” (page 58 lines 1-2). Also, as stated above, McAleer is relied upon for the teaching of a biochip (see rejection above). Therefore, Glimcher in view of McAleer address the method of claim 1 (see rejection above for the complete analysis). Applicant further argues that “Moreover, there is no indication provided by Glimcher to immobilise two different antibodies, each specific to an isoform, at discrete locations on a biochip” (page 9 para. 5). However, as stated above, new grounds of rejection are set forth in view of Glimcher and McAleer (see rejection above). Applicant further argues that “[t]he Examiner utilizes hindsight in citing McAleer as, again, there is no suggestion nor even hint in Glimcher that a biochip should be used. McAleer discloses a semiautomated "Evidence Investigator'' used for simultaneous measurement of soluble adhesion molecules. … The skilled person has no reason to depart from this teaching, and thus would not turn to McAleer” (page 10 para. 4). However, McAleer provides motivation for using the biochip (see rejection above). Applicant further argues that “the skilled person would not arrive at the claimed sandwich multianalyte immunoassay array, whether considering Glimcher alone or in combination with any of the cited documents” (page 10 para. 6). However, contrary to Applicant’s argument, the skilled person would arrive at the claimed method when considering Glimcher in combination with McAleer as set forth above (see rejection above).
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FERNANDO IVICH whose telephone number is (703)756-5386. The examiner can normally be reached M-F 9:30-6:00 (E.T.).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gregory S. Emch can be reached at (571) 272-8149. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/Fernando Ivich/Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678