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Withdrawn Rejection
The rejection of claims 3-4, 8-16, 21 and 29 under 35 U.S.C. 112(b) is withdrawn in response to the amendments.
Priority
The present application was filed as a proper National Stage (371) entry of PCT Application No. PCT/ EP2020/072240, filed 06/30/2022. Acknowledgment is also made of applicant's claim for foreign priority under 35 U.S.C. 119(a)-(d) to Application No. 102019000014571, filed on 08/09/2019 in Italy. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Status of the Claims
Claims 1, 3-4, 8-25 and 27-29 are pending; claims 3-4, 8-12, 14-16, 18-19, 21-2 and 29 are amended, claims 2, 5-7 and 26 are canceled; no claims are withdrawn. Claims 1, 3-4, 8-25 and 27-29 are examined below.
New Objection
Claim Objections
Claims 10 and 19 are objected to because of the following informalities:
In claim 10 lines 1-3, "wherein the autoimmune is Amyotrophic Lateral Sclerosis-ALS" appears to be a typographical error, namely it is suggested that "wherein the autoimmune is Amyotrophic Lateral Sclerosis-ALS" read as "wherein the autoimmune disease is Amyotrophic Lateral Sclerosis-ALS" (emphasis added).
In claim 19 lines 4-5, “in mouse protein” appears to be a typographical error, namely it is suggested that “in mouse protein” read as “in a mouse protein” (emphasis added).
Appropriate correction is required.
Maintained Rejections
Claim Rejections - 35 USC § 112
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 18-19 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 18 recites “further comprising querying a database of mouse protein sequences using the amino acid sequence of each lgG-bound peptide identified in step (e) as a query in order to select one or more mouse proteins comprising a peptide sequence which has an amino acid sequence identity to the amino acid sequence of each of the queried peptides comprised
between 67% and 100%, wherein the mouse protein sequences are from a mouse belonging to a species which is different from the first congenic mouse and second congenic mouse”.
However, it is not clear how “the mouse protein sequences are from a mouse belonging to a species which is different from the first congenic mouse and second congenic mouse”. Notably a mouse is the same species as the first congenic mouse and second congenic mouse, i.e. they are both mice. A person having ordinary skill in the art would not be capable of recognizing the metes and bounds of the claim.
Claim 19 recites “further comprising identifying as peptide antigens relevant to the non-autoimmune disease the peptide sequences which have from 67% to 100% amino acid sequence identity and which are comprised in mouse protein expressed in a tissue affected by the non-autoimmune disease”.
However, “identifying as peptide antigens relevant to the non-autoimmune disease the peptide sequences which have from 67% to 100% amino acid sequence identity” is not clear because there is no other recited peptide sequence to be used in the comparison. A person having ordinary skill in the art would not know how to identify as peptide antigens relevant to the non-autoimmune disease the “peptide sequences which have from 67% to 100% amino acid sequence identity” because the amino acid sequence identity by itself does not provide enough guidance to perform the identifying step.
For these reasons, the claims are indefinite.
Maintained Rejections
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.
Claims 1, 11-13, 17, 20 and 24-25 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Restrepo et al. ANN NEUROL 2011;70:286–295 ("Restrepo") as evidenced by Dickson American Journal of Pathology, Vol. 164, No. 4, April 2004, Jackson-B6C3F1/J (retrieved online https://www.jax.org/strain/100010# 11/28/2025), Jackson- B6;C3-Tg(APPswe,PSEN1dE9)85Dbo/Mmjax (retrieved online https://www.jax.org/strain/004462 on 111/28/2025), Mayo Clinic Alzheimer’s disease (retrieved online https://www.mayoclinic.org/diseases-conditions/alzheimers-disease/symptoms-causes/syc-20350447#:~:text=Sex%20assigned%20at%20birth,healthcare%20appointments%20to%20monitor%20symptoms. On 11/26/2025).
Regarding claim 1, Restrepo teaches a method for identifying a peptide antigen (“the ability of an antibody-profiling technology to characterize AD and screen for peptides that may be used for a simple diagnostic test” Abstract, “We identified a set of random peptides from the
array with the highest binding by particular plasma samples, allowing plans for development of arrays with reduced number of peptides, or individual enzyme-linked immunosorbent assays (ELISAs) using random peptides as antigen” page 293 col. 1 para. 2) associated with a non-autoimmune disease (“Application of immunosignatures to the assessment of Alzheimer’s disease” Title) using congenic mice (“TG mice exhibited a distinct immunoprofile compared to nontransgenic littermates” Abstract), said method comprising the following steps: (a) providing a first congenic mouse and a second congenic mouse, wherein the first congenic mouse and the second congenic mouse are genetically identical except the first congenic mouse is affected by the non-autoimmune disease and the second congenic mouse is not affected by the non-autoimmune disease (“APPswe/PSEN1-1dE9 transgenic (TG) mice were purchased from Jackson Laboratories (Bar Arbor, ME), as well as nontransgenic controls (B6C3F1/J)” page 287 col. 2 para. 2, “These mice are engineered with 2 human mutations found in familial AD, affecting the amyloid precursor protein (APP) and presenilin-1 (PSEN1) genes. The resulting phenotype is well characterized, consisting of progressive amyloidosis involving cerebral cortex, astrocytosis, neurodegeneration, and cognitive impairment, beginning at about 6 months of age” page 288 col. 1 para. 2). Note that although Restrepo fails to use the language “congenic” and “genetically identical” the teaching of “nontransgenic littermates” inherently provides the use of congenic mice, more specifically, genetically identical except the first congenic mouse is affected by the non-autoimmune disease and the second congenic mouse is not affected by the non-autoimmune disease. As evidenced by Dickson “nontransgenic littermates” are preferable as controls in experiments involving APPswe/PSEN1-1dE9 transgenic mice because “they control for genetic background” (page 1145 col. 1 para. 2), which reads on the claim, i.e. genetically identical except the first congenic mouse is affected by the non-autoimmune disease and the second congenic mouse is not affected by the non-autoimmune disease. Dickson further suggests that nontransgenic littermates are congenic when “back-crossing onto standard laboratory strains” (page 1145 col. 1 para. 4). As evidenced by Jackson-B6C3F1/J, the nontransgenic littermate control of Restrepo is the backcrossing “between C57BL/6J females (B6) and C3H/HeJ males (C3)” (page 1 para. 1). And as evidenced by Jackson- B6;C3-Tg(APPswe,PSEN1dE9)85Dbo/Mmjax, the transgenic mouse used by Restrepo is a cross between B6 and C3 (see What Does This Nomenclature Mean? Page 1). Therefore, the transgenic mouse and nontransgenic littermate control taught by Restrepo are reasonably interpreted as the first and second congenic mouse of the instant claim. Restrepo further teaches (b) contacting a first biological blood, serum or plasma fluid sample comprising a plurality of IgG immunoglobulins from the first congenic mouse with a microarray having surface affixed thereon a plurality of isolated or synthetic antigenic peptides, wherein each of the plurality of isolated or synthetic antigenic peptides: (i) has a pre-determined location on the surface of the microarray and (ii) comprises an amino acid sequence of a protein from the first congenic mouse (“FIGURE 2: Immunosignature of transgenic mice. (A) Heat map of 113 microarray peptides that can discriminate between plasma signatures of APPswe/PSEN1-1dE9 transgenic (TG) mice (n 5 5) and nontransgenic B6C3F1/J littermates (n 5 4). Blue tones indicate low binding and red colors indicate avid binding (more antibodies bound per spot), whereas yellow hues designate intermediate binding. Note that plasma pools segregate with individual samples” page 290, “Our microarray consists of a solid phase with 10,000 random sequence 20-mers covalently attached to glass slides, which can be probed with any antibody of interest” page 286 col. 2 para. 2). Note that although Restrepo fails to use the language “contacting”, the teaching of binding of plasma antibodies to the microarray inherently provides a step of “contacting”. Restrepo further teaches (c) detecting the binding of one or more of the IgG immunoglobulins present in the first biological fluid sample with one or more of the affixed isolated or synthetic antigenic peptides on the microarray to provide a first IgG-bound peptide profile (“A biotinylated, species-specific antibody was allowed to incubate with the slides, followed by 5lM Streptavidin conjugated to Alexa 555. Arrays were scanned with a laser to generate digital images that were processed using GenePix Pro v6 (Molecular Devices, Sunnyvale, CA)… Biotinylated antibodies targeting rabbit, mouse, goat, and human immunoglobulin G (IgG) were purchased from Bethyl” page 287 col. 1 para. 2 and col. 2 para. 1); (d) comparing the first IgG-bound peptide profile to a second IgG-bound peptide profile generated by contacting the microarray as defined in step (b) with a second biological blood, serum or plasma fluid sample comprising IgG immunoglobulins from the second congenic mouse, wherein detecting the binding of one or more of the lgG immunoglobulins present in the second biological blood, serum or plasma fluid sample to one or more of the affixed isolated or synthetic antigenic peptides on the microarray provides a second lgG-bound peptide profile (“The microarray signature of 10-month-old TG mice was different from 4 age-matched B6C3F1/J nontransgenic littermates (Fig 2A, B)” page 288 col. 1 para. 2); (e) identifying which, if any, of the microarray bound peptides are bound by IgG antibodies derived from the first congenic mouse and are not bound by IgG antibodies derived from the second congenic mouse (Fig. 2). Furthermore, Restrepo teaches wherein identifying which, if any, of the microarray bound peptides bound by lgG antibodies derived from the first congenic mouse and not bound by lgG antibodies derived from the second congenic mouse identifies a peptide that can be used as a marker or therapeutic antigen for the non-autoimmune disease (“We propose that ‘‘immunosignaturing’’ technology may have potential as a diagnostic tool in AD” Abstract).
Regarding claims 11-13, Restrepo teaches wherein the non-autoimmune disease is Alzheimer’s Disease (Title). Restrepo further teaches that Alzheimer’s disease is a type of dementia (“diagnosing specific dementias” page 286 col. 1 para. 1). As evidenced by Mayo clinic, Alzheimer’s disease is a dementia that is an age-related dementia (“Alzheimer's disease is the most common cause of dementia” page 1 para. 1, “Older age is the strongest known risk factor for Alzheimer's disease” page 7 para. 2).
Regarding claim 17, Restrepo teaches wherein the nonautoimmune disease is a human or veterinary non-autoimmune disease (Title, Abstract).
Regarding claim 20, Restrepo teaches wherein the human or veterinary non-autoimmune disease is a neurodegenerative or a neurological disease, an old-age related disease and any combination thereof (Title, Abstract). Note that as evidenced by Mayo clinic, Alzheimer’s disease an old-age-related dementia (page 1 para. 1, page 7 para. 2).
Regarding claim 24-25, Restrepo teaches wherein the neurodegenerative or the neurological disease is Alzheimer’s disease and a dementia (Title, Abstract, page 286 col. 1 para. 1).
Maintained 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 10, 14-15, 18-19, 23 and 27-28 are rejected under 35 U.S.C. 103 as being unpatentable over Restrepo as evidenced by Dickson, Jackson-B6C3F1/J and Jackson- B6;C3-Tg(APPswe,PSEN1dE9)85Dbo/Mmjax as applied to claim 1 above, and further in view of in view of Kohli et. al. (WO2008/068024A2) (Cite No. N in PTO 892 10/23/2024).
Regarding claims 10, 14-15, 23 and 27-28, Restrepo fails to teach wherein the neurodegenerative or the neurological disease is Amyotrophic Lateral Sclerosis-ALS, Mild Cognitive Decline, or Parkinson’s Disease.
Kohli et. al. teach a method of identifying molecules interacting with proteins associated with Alzheimer’s disease (Abstract) comprising “microarrays loaded with antigens of or antibodies specific for one or more of the neurological disorder-associated proteins” (page 46, lines 33-34), similar to Restrepo and the instant application. Kohli et al. further teach to identify proteins associated with Alzheimer’s disease using transgenic mouse models of a neurological disorder (claims 1-11 of Kohli et al.) and a nontransgenic littermate control mouse to compare between health and disease (page 90, line 8, “in the transgenic mouse of the present invention expressing APP-TAP-AICD (see Example 2), PCR-negative littermates were used as negative controls” page 103 lines 20-21). Kohli et al. further teach that the mouse models can be adapted to other disorders such as “Parkinson's disease…amyotrophic lateral sclerosis…mild cognitive impairment” (page 44 lines 21-30). Kohli et al further teach that “there is still a need for therapeutic and diagnostic means for the treatment of AD as well as other disorders associated with APP” (page 2 lines 15-16). Kohli et al. further teach that the mouse models are used to study neurodegenerative or neurological diseases (page 44, lines 21-23) and for screening drugs that may be useful in the treatment of neurodegenerative or neurological diseases (page 45, lines 18-26). Kohli et al. further recite that “[t]he practice of the present invention will employ, unless otherwise indicated, conventional techniques of cell biology, cell culture, molecular biology, transgenic biology, microbiology, recombinant DNA, and immunology, which are within the skill of the art” (page 112, lines 9-11).
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 Restrepo to adapt the Alzheimer’s Disease (AD) mouse model for a mouse model of Amyotrophic Lateral Sclerosis-ALS, Mild Cognitive Decline (MCD) or Parkinson’s Disease (PD) taught by Kohli et al., thereby arriving at the present claim, because Kohli et. al. motivate the use of mouse models to study neurodegenerative or neurological diseases (page 44, lines 21-23) and for screening drugs that may be useful in the treatment of neurodegenerative or neurological diseases (page 45, lines 18-26). One would have been motivated to try picking ALS, MCD or PD from the finite list of neurodegenerative or neurological disorders taught by Kohli et al. because Kohli et al. teach that there is still a need to study therapeutic and diagnostic means for diseases associated with amyloid precursor protein. A person having ordinary skill in the art would have had a reasonable expectation of success given that Kohli et al. teach the use of conventional techniques within the skill of the art.
Regarding claims 18-19, although the claims are indefinite (see 112b rejection above), in the interest of compact prosecution, claim 18 is interpreted to recite “…a species different from mouse” (emphasis added), and claim 19 is interpreted to recite “…the peptide sequences which have from 67% to 100% amino acid sequence identity to the amino acid sequence of each of the queried peptides selected in claim 18…” (emphasis added).
Restrepo fails to teach further comprising querying a database of animal protein sequences using the amino acid sequence of each lgG-bound peptide identified in step (e) as a query in order to select one or more animal proteins comprising a peptide sequence which has an amino acid sequence identity to the amino acid sequence of each of the queried peptides comprised between 67% and 100%, wherein the animal protein sequences are from an animal belonging to a species which is different from the mouse, further comprising identifying as peptide antigens relevant to the non-autoimmune disease the peptide sequences which have from 67% to 100% amino acid sequence identity to the amino acid sequence of each of the queried peptides selected in claim 18 and which are comprised in an animal protein expressed in a tissue affected by the non-autoimmune disease.
Kohli et al. disclose querying a database ("the person skilled in the art may identify agents to be used in accordance with the present invention by screening so-called primary databases" page 36, lines 29-33) of animal protein sequences using the amino acid sequence of each IgG-bound peptide identified in step (e) as the query in order to select one or more animal proteins (“besides the use of newly identified compounds the present invention also contemplates the validation and thus the use of agents which are known to bind to any one of said APP interacting proteins” page 36, lines 25-27) comprising a peptide sequence which has an amino acid sequence identity to the amino acid sequence of each of the queried peptides comprised between 67% and 100%, wherein the animal protein sequences are from an animal belonging to a species which is different from mouse (“also the human counterparts of the mouse proteins can be easily identified” page 37, line 3); and identifying as peptide antigens relevant to the non-autoimmune disease the peptide sequences which have from 67% to 100% amino acid sequence identity to the amino acid sequence of each of the queried peptides selected and which are comprised in an animal protein expressed in a tissue affected by the non-autoimmune disease (“in particular of Alzheimer's disease” page 38, lines 6-12). See specifically Kohli et al. teach at page 128, lines 26-34 the use of software to search peptide databases “that allows: scoring of peptide matches” using a Gaussian Model (page 129, lines 1-10), thereby denoting a desired probability threshold. Furthermore, by teaching that protein variants in reference to their invention “comprise a sequence that has at least about 80% sequence identity” (“preferably at least about 95% sequence identity” page 15, lines 20-23) and also reciting that “the person skilled in the art may identify agents…in databases” (page 36, lines 32-34), the 80 and/or 95% as disclosed by Kohli et al addresses the claimed range, identifying variants between 67% and 100% of sequence identity of target queries in databases. See MPEP 2131.03, a specific example in the prior art which is within the claimed range, addresses the claimed range. As a result, the disclosed value, addresses the claim.
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 Restrepo to include the querying and identifying steps of Kohli et al., namely using, mice, a mouse model of disease and searching in the literature (querying a database of animal protein sequences) for related proteins that have been identified by the invention (page 36, lines 25-29), thereby arriving at a method comprising the steps as recited in the present claim, because Kohli et. al. teach that one may identify proteins in the databases that are known but have not been considered useful (page 36, lines 25-27), as well as finding “further information with respect to regulation of the corresponding genes” (page 37, lines 4-5), thereby motivating the common artisan. The modification would have been an obvious matter of applying a known technique to a known method. Specifically, the prior art contained the base method as taught by Restrepo and Kohli et al.. The prior art also contained the known technique of identifying proteins in a database that are already known, but have not been yet considered useful, specifically performing the query to identify possible candidates of similar identity. One having ordinary skill would have found it obvious to apply this technique to the method of Restrepo and the results of the modification would have been predictable, namely one would expect to uncover peptides of similar identity for the proteins in humans (i.e., the human counterparts), that is for an animal belonging to a species which is different from the mouse (as currently interpreted). Furthermore, Kohli et al. teaches that using mice and a mouse model of disease substantially reduces the risk of false positives as taught by Kohli et al. (page 3, lines 16-17).
The common artisan would have had a reasonable expectation of success because Kohli et. al. teach using databases to "easily" identify the human counterparts of the identified mouse proteins (page 37, line 3). Furthermore, the common artisan would have had a reasonable expectation of success because Kohli et. al. teach it is within the ordinary skill in the art to identify proteins associated with health and disease (page 3, lines 12-13) and Kohli et. al. teach mouse models of diseases, e.g., mice that express brain amyloid, tau or α-synuclein pathologies (page 3, lines 15-16).
Claims 3-4, 8-9 and 21-22 are rejected under 35 U.S.C. 103 as being unpatentable over Restrepo as evidenced by Dickson, Jackson-B6C3F1/J and Jackson- B6;C3-Tg(APPswe,PSEN1dE9)85Dbo/Mmjax, as applied to claim 1 above, and further in view of Desauvage et. al. (WO2008042469) (Cite No. O in PTO 892 10/23/2024).
Restrepo in view of the cited art teach a method substantially as claimed (see as discussed above).
However, regarding claim 3, Restrepo fails to teach wherein the non-autoimmune disease is heart failure, namely is heart failure that is hemodynamically induced heart failure (claim 3).
Desauvage et. al. teach mouse models of heart failure (HF), of a cardiac disease, a vascular disease, atherosclerosis, vascular stenosis, a metabolic disease (page 12, lines 13-16), and obesity (page 78, line 25) for peptide antigen screening (page 219, lines 1-3; and claims 1, 3 and 18). Desauvage et. al. suggest wherein the heart failure is hemodynamically induced heart failure (page 68, lines 3-8). Desauvage et al. further suggest that the mouse models can identify new therapeutics which is a current trend in the field (“[e]fforts are being undertaken by both industry and academia to identify new, native receptor or membrane-bound proteins” page 2 lines 18-19).
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 Restrepo, specifically including a transgenic mouse model of heart failure, wherein the heart failure is hemodynamically induced heart failure taught by Desauvage et. al. because Desauvage et. al. motivates the use of transgenic mouse models of heart failure, wherein heart failure is hemodynamically-induced heart failure in order to receive the expected benefit of "providing valuable identification and discovery of therapeutics and/or treatments useful in the prevention, amelioration or correction of diseases or disfunctions" (Abstract). Although Desauvage teaches hemodynamically induced heart failure from a finite list of other non-autoimmune diseases, it would have been obvious to try picking hemodynamically induced heart failure because Desauvage et al. teach that there is a need to identify new therapeutics in the field. Therefore, one would have been motivated to apply the method to a disease that is heart failure to screen for drugs to treat heart failure, wherein heart failure is hemodynamically-induced heart failure.
The common artisan would have had a reasonable expectation of success because Desauvage et. al. teach transgenic mouse models of non-autoimmune disease (Abstract) and Restrepo also teaches a transgenic mouse model of non-autoimmune disease.
Regarding claim 4, Restrepo fails to teach wherein the combination of non-autoimmune diseases comprises a multimorbidity condition.
Desauvage et. al. suggest wherein the combination of non-autoimmune diseases comprises a multimorbidity condition (page 78, lines 24-25 “coronary artery diseases, diabetes and/or obesity”). Note that by disclosing “coronary artery diseases, diabetes and/or obesity” the definition of multimorbidity is addressed as per page 14, lines 25-27 of the instant disclosure “multimorbidity is a clinical situation wherein a patient suffers simultaneously from more than one of the following groups of ailments: cardiovascular, neurological, oncological and metabolic disease”. Because of the language “more than one” by the instant disclosure, the definition of multimorbidity allows for as little as two simultaneous ailments. Therefore, “coronary artery diseases, diabetes and obesity” disclosed by Desauvage et. al. addresses the multimorbidity scenario of having a cardiovascular and a metabolic disease simultaneously.
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 Restrepo to include the mouse models of multimorbidity taught by Desauvage et. al. because Desauvage et. al. motivate the use of non-human transgenic animals with a lipid metabolic disorder phenotype (multimorbidity) to identify associations between peptides and disease (claims 1 and 3). Although Desauvage teaches multimorbidity from a finite list of other non-autoimmune diseases, it would have been obvious to try picking multimorbidity because Desauvage et al. teach that there is a need to identify new therapeutics in the field, therefore identifying associations between peptides and disease would be helpful. A person having ordinary skill in the art would have had a reasonable expectation of success because both Restrepo and Desauvage et al. teach transgenic mouse models of non-autoimmune disease.
Regarding claims 8 and 21, Restrepo fails to teach wherein the metabolic disease is a non- type 1 diabetes.
Desauvage et. al. suggest wherein the metabolic disease is a non- type 1 diabetes (page 74, line 3).
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 Restrepo to include the mouse models of non-type-1 diabetes, taught by Desauvage et. al. because Desauvage et. al. motivates the use of mouse models for "providing valuable identification and discovery of therapeutics and/or treatments useful in the prevention, amelioration or correction of diseases or disfunctions" (Abstract). Although Desauvage teaches non- type 1 diabetes from a finite list of other non-autoimmune diseases, it would have been obvious to try picking non- type 1 diabetes because Desauvage et al. teach that there is a need to identify new therapeutics in the field. Therefore, one would be motivated to apply the method to a disease that is non-type I diabetes to screen for drugs to treat metabolic disease, wherein metabolic disease is a non- type 1 diabetes.
The common artisan would have had a reasonable expectation of success because Desauvage et. al. teach transgenic mouse models of non-autoimmune disease (Abstract) and Restrepo also teaches a transgenic mouse model of non-autoimmune disease.
Regarding claims 9 and 22, Restrepo fails to teach wherein the metabolic disease is a metabolic syndrome.
Desauvage et. al. suggest wherein the metabolic disease is a metabolic syndrome (page 3, lines 21-22 ). Note that Desauvage et. al. discloses “abnormal metabolic disorders” which is reasonably interpreted as a metabolic syndrome as per page 3, lines 30-31 of the instant disclosure.
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 Restrepo to include the mouse models of metabolic disease, wherein metabolic disease is a metabolic syndrome, taught by Desauvage et. al. because Desauvage et. al. motivates the use of mouse models for "providing valuable identification and discovery of therapeutics and/or treatments useful in the prevention, amelioration or correction of diseases or disfunctions" (Abstract). Although Desauvage teaches metabolic syndrome from a finite list of other non-autoimmune diseases, it would have been obvious to try picking metabolic syndrome because Desauvage et al. teach that there is a need to identify new therapeutics in the field. Therefore, one would be motivated to apply the method to a disease that is metabolic disease to screen for drugs to treat metabolic disease, wherein metabolic disease is metabolic syndrome.
The common artisan would have had a reasonable expectation of success because Desauvage et. al. teach transgenic mouse models of non-autoimmune disease (Abstract) and Restrepo also teaches a transgenic mouse model of non-autoimmune disease.
Claims 16 and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Restrepo as evidenced by Dickson, Jackson-B6C3F1/J and Jackson- B6;C3-Tg(APPswe,PSEN1dE9)85Dbo/Mmjax, as applied to claim 1 above, and further in view of Lohse and Lorenz (WO2010060972) (Cite No. P in PTO 892) and Kohli et al. (Cite No. N in PTO 892).
Regarding claim 16 and 29, Restrepo fails to teach wherein the mouse model is a Transverse Aortic Constriction (TAC) mouse model.
Lohse and Lorenz teach an antibody assay (Abstract) for identifying a peptide related to heart failure (page 14, lines 21-30) and used a Transverse Aortic Constriction (TAC) mouse model (page 29, lines 20-28) to test and validate their invention.
Kohli et. al. teach it is within the ordinary skill in the art to use a mouse model for testing and validating potential medicine (page 44, lines 15-16).
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 Restrepo to include the Transverse Aortic Constriction (TAC) mouse model limitation taught by Lohse and Lorenz, thereby arriving at claims 16 and 29, because Lohse and Lorenz show that their antibody assay identified a difference in Erk1/2 phosphorylation expression in TAC vs. control mice (“co-immunoprecipitation… observed in…(TAC) but not in control” page 32, lines 14-17, Fig. 1(g)). Therefore, Lohse and Lorenz motivate the use of the TAC model since it does generate expected results. Although Lohse and Lorenz do not teach using a blood, serum, or plasma body fluid sample and instead teach using “heart lysates” (page 32, line 15), the common artisan would have had a reasonable expectation of success because Kohli et. al. teach it is within the ordinary skill in the art to use a mouse model for testing and validating potential medicine and Lohse and Lorenz teach a mouse model for testing a potential heart-disease diagnostic (Abstract and claim 13).
One would have been motivated to make such a modification in order to receive the expected benefit of diagnosing heart disease as taught by Lohse and Lorenz (Abstract). A person having ordinary skill in the art would have had a reasonable expectation of success given that both Restrepo and Lohse and Lorenz teach a method for identifying a peptide antigen associated with a non-autoimmune disease using mouse models.
Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Paull et al. Current Opinion in Chemical Engineering 2018, 19:21–26 https://doi.org/10.1016/j.coche.2017.12.001 (“Paull”). Paull teaches subject matter pertinent to at least claims 1, 11, 17-20 and 24.
Paull teaches that “Immunosignaturing uses 104–105 random peptides displayed in a microarray format to profile the antibody repertoire. Immunosignaturing has been used to profile the antibody repertoires of transgenic mice with an Alzheimer’s disease (AD) phenotype to identify distinct signatures at different time points in disease progression. Interestingly, these results suggested that humans with AD had detectable immunological similarity despite having distinct personal antibody repertoires. In other studies, immunosignatures differentiated between similar pancreatic diseases, between multiple cancers and infectious diseases, and between myalgic encephalomyelitis disease subjects and controls. Microarrays were also used to successfully classify more than 1500 serum samples into 15 disease groups…Subsequences have been used instead of sequences in BLAST searches to identify potential associations between epitopes and pathogen antigens. Researchers determined that in a BLAST search of pathogen proteins, the true antigen can be resolved if a pair of pentamers exactly match the antigen or a pair of heptamers have 80% identity” (page 23 col. 1 para. 2 and col. 2 paras. 2-3). Paull, therefore, suggests using a peptide microarray to detect antibodies from serum samples of transgenic mice and subsequently BLAST searching the peptides sequences to identify the associated human pathogen antigen when there is 80% of sequence identity.
Response to Arguments
11. Applicant's arguments filed 4/8/2026 have been fully considered but they are not persuasive.
Regarding the 112b rejections,
Applicant argues that “because the instant amendment addresses the section §112(b), or §112, second paragraph, issues raised by the Office, the rejection under §112(b), or section 112, second paragraph, can be properly withdrawn” (page 9 para. 3).
However, the amendments to claims 18-19 fail to address the 112b issues outlined in the Office Action (12/10/2025). Therefore, the rejection of claims 18-19 is maintained (see rejection above).
Regarding the 102 rejections,
Applicant argues that “this claimed invention encompasses use of identical congenic (i.e. genetically identical) mice suffering from a non-autoimmune disease, and that this by necessity means that the disease model examined in this claimed invention was induced by a non-genetic means: i.e., exclusively by application of a physical treatment, immunization, or pharmacological treatment on genetically identical mice; and the congenic mouse model of this claimed invention is not a genetically-engineered disease model” (page 9 last paragraph).
However, the claims are not limited to disease models induced by non-genetic means. In fact the specification suggests that the invention encompasses mouse models of disease induced by genetic means (“Other non-limiting examples of mouse models of disease are chronic heart failure after myocardial infarction or genetically-induced models of dilated cardiomyopathy” page 12 lines 15-16).
Declaration under 37 C.F.R. § 1.132
The declaration under 37 C.F.R. § 1.132 filed 9/16/2025, and the declaration under 37 C.F.R. § 1.132 filed 4/08/2026, i.e. the first and second declaration by Dr. Marinos Kallikourdis, are sufficient to overcome the outstanding rejections under 102.
Dr. Marinos Kallikourdis declares that “one of skill in the art at the time of the invention, after reading Restrepo, Dickson, and the JacksonB6 reference, would not consider Restrepo's use of transgenic mouse in their experiments to be equivalent to this invention's use of congenic mice (“page 4 para. 1 of Declaration 4/8/2026).
However, this argument is not persuasive given that it does not address the rejection over Restrepo as evidenced by Dickson, JacksonB6C3F1/J and Jackson- B6;C3-Tg(APPswe,PSEN1dE9)85Dbo/Mmjax reference (see rejection above). In short, the transgenic mouse and non-transgenic littermate control taught by Restrepo are reasonably interpreted as anticipating the claim as currently recited “genetically identical except the first congenic mouse is affected by the non-autoimmune disease and the second congenic mouse is not affected by the non-autoimmune disease”. Dickson suggests that nontransgenic littermates are congenic when “back-crossing onto standard laboratory strains” (page 1145 col. 1 para. 4). As evidenced by Jackson-B6C3F1/J and Jackson- B6;C3-Tg(APPswe,PSEN1dE9)85Dbo/Mmjax, the transgenic mouse and nontransgenic littermate control mouse taught by Restrepo are back-crossed onto standard laboratory strains, therefore, these mice are reasonably interpreted as the first and second congenic mouse, wherein the first congenic mouse and the second congenic mouse are
genetically identical except the first congenic mouse is affected by the nonautoimmune disease and the second congenic mouse is not affected by the non-autoimmune disease
Dr. Marinos Kallikourdis declares that “the congenic mouse model of this claimed invention is not a genetically-engineered disease model, as is the case with Restepo, who used transgenic mice in their experiments. In other words, Restepo use a specific, genetically-driven disease, that their trans-genic mouse suffers from. Our invention features congenic and not trans-genic mice. The diseases our invention applies to are non-autoimmune and not genetically-driven, as all mice in our invention are genetically identical” (page 4 para. 2 of Declaration 4/8/2026).
However, as explained in the rejection above, although Restrepo uses a transgenic mouse and a non-transgenic littermate control, these reasonably anticipate step (a) “providing a first congenic mouse and a second congenic mouse, wherein the first congenic mouse and the second congenic mouse are genetically identical except the first congenic mouse is affected by the nonautoimmune disease and the second congenic mouse is not affected by the non-autoimmune disease”.
Dr. Marinos Kallikourdis further declares that “Restepo only teaches use of transgenic (TG) mice which develop a disease, and Restepo compares the TG mice data to wild-type (non-transgenic) C57 mice, which do not develop the disease; and, thus Restepo only teaches (and uses) a genetically-driven disease model which would inherently give different experimental results if one of skill would practice the claimed methods of this invention (using the transgenic mouse) as compared to use of congenic mice as claimed in this application” (page 5 para. 1 of Declaration 4/8/2026).
However, the non-transgenic littermate control taught by Restrepo is the “B6C3F1/J littermates” (see Restrepo page 287 col. 2 para. 2), not the “C57 mice” declared. As explained above, the B6C3F1/J littermates are reasonably interpreted as being genetically identical to the transgenic mouse expect that the transgenic mouse is affected by the non-autoimmune disease and the non-transgenic mouse (B6C3F1/J littermate) is not affected by the non-autoimmune disease. The art also teaches that these two mice are proper controls because they have the same genetic background, which anticipates “(a) providing a first congenic mouse and a second congenic mouse, wherein the first congenic mouse and the second congenic mouse are genetically identical except the first congenic mouse is affected by the nonautoimmune disease and the second congenic mouse is not affected by the non-autoimmune disease”.
Dr. Marinos Kallikourdis further declares that “Dickson does not in fact teach use of congenic mice as claimed in this application as experimental animals, but only as controls. Thus, one of skill would understand that Dickson does not cure the defect in Restepo in that Dickson does not teach use of congenic mice as claimed in this application as experimental animals” (page 5 para. 2 of Declaration 4/8/2026).
However, the claim is not limited to the second congenic mouse not being a control. In fact, the second congenic mouse claimed reads on a control mouse because it is not affected by the nonautoimmune disease.
Dr. Marinos Kallikourdis further declares that “Restrepo uses transgenic mice as experimental animals, and one of skill would understand that the transgenic experimental animals used by Restrepo inherently give different experimental results if one of skill would practice the claimed methods of this invention (using Restrepo type transgenic mouse) as compared to use of congenic mice as claimed in this application” (page 5 para. 3 of Declaration 4/8/2026).
However, a proper analysis was done, see rejection above, explaining that the transgenic mouse used by Restrepo, i.e. “APPswe,PSEN1dE9” and the “B6C3F1/J littermates” effectively control for genetic background and thus are not expected to give unreliable experimental results.
Dr. Marinos Kallikourdis further declares that “one of skill in the art at the time of this invention, after reading Kohli, cited for teaching inter alia methods for identifying molecules with proteins associated with Alzheimer's disease comprising use of microarrays, and notably transgenic mice, would not have been motivated to modify Restrepo, Dickson, and the Jackson-B6 reference, to teach the methods of this claimed invention using congenic mice” (page 6 para. 1 of Declaration 4/8/2026).
However, this argument is not persuasive as it does not address the obviousness analysis made above. The rejection is maintained (see rejection above).
Dr. Marinos Kallikourdis further declares that “one of skill in the art at the time of this invention, after reading Desauvage, cited for teaching inter alia methods using mouse models of heart failure, of a cardiac disease, a vascular disease, etc for peptide antigen screening, would not have been motivated to modify Restrepo, Dickson, and the Jackson-B6 reference, to teach the methods of this claimed invention using only congenic mice for both the diseased group and the control group” (page 6 para. 2 of Declaration 4/8/2026).
However, this argument is not persuasive as it does not address the obviousness analysis made above. The rejection is maintained (see rejection above).
Dr. Marinos Kallikourdis further declares that “one of skill in the art at the time of this invention, after reading Lohse and Lorenz, cited for teaching inter alia methods using an antibody assay for identifying a peptide related to heart failure using a Transverse Aortic Constriction mouse model (and use of transgenic mice, see page 25, of Lohse and Lorenz, WO 2010/060972), would not have been motivated to modify Restrepo, Dickson, and the Jackson-B6 reference, to teach the methods of this claimed invention using only congenic mice” (page 6 para. 3 of Declaration 4/8/2026).
However, this argument is not persuasive as it does not address the obviousness analysis made above. The rejection is maintained (see rejection above).
Conclusion
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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/Fernando Ivich/Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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