DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 03/23/2026 has been entered.
Claim Status
Claim 1 has been amended as requested in the amendment filed on 03/23/2026. Following the amendment, claims 1-8 are pending in the instant application.
Claims 1-8 are under examination in the instant office action.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Claims 1-8 have an effective filing date of November 29, 2010 corresponding to PRO 61/417,559.
Claim Interpretation
With regard to presently amended claim 1, the claim currently recites “detecting the presence of a peptide having an N-terminal amino acid sequence FAEDVG (SEQ ID NO: 1)”. This limitation is being interpreted such that any peptide comprising the sequence FAEDVG at the N-terminus, wherein the phenylalanine residue (i.e., F) is the first residue of said peptide, meeting the limitation; the peptide may comprise any number of C-terminal residues following the sequence corresponding to FAEDVG.
Claim Rejections - 35 USC § 103 - New
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.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The factual inquiries for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
It is noted that the new grounds of rejection below are based on the previous rejections of record, wherein additional prior art is included to address Applicant’s arguments.
Claims 1-8 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over US 9,625,474 (herein after referred to as "Johnsen") in view of non-patent literature by Hideaki Hamazaki (FEBS Letters, 1996, 396, 139-142; herein after referred to as “Hamazaki”), non-patent literature by Fiala et. al. (Journal of Alzheimer’s Disease, 2007, 11, 457-463; herein after referred to as “Fiala”), US 2006/0057702 A1 (previously cited on PTO-892; herein after referred to as "Rosenthal"), and US 2005/0169925 A1 (previously cited on PTO-892; herein after referred to as "Bardroff").
With regard to claim 1, Johnsen identifies that there is still no reliable means for detecting the early stages of AD, even though these early periods may tum out to be clinically valuable for implementation of disease modifying therapies; this is significant because, at later stages, the widespread damage caused by AD is most likely irreversible and therefore early
detection of AD is important to its effective treatment (Column 2, Lines 10-16). Johnsen teaches a method of detecting the presence, or monitoring the severity of a condition characterized by the presence of fragments of a marker protein in the brain of a patient. The method comprises: (i) providing a sample comprising macrophages obtained from the patient; and (ii) detecting the presence of the marker protein or fragments thereof in the macrophages (Abstract; see also claim 1). It is preferred that: the condition is Alzheimer's Disease and the marker protein is the Aβ peptide; the condition is Parkinson's Disease and the marker protein is ubiquitin; the condition is Multiple Sclerosis and the marker protein is myelin basic protein; the condition is FrontoTemporal Dementia and the marker protein is the tau protein; or the condition is Amyotrophic Lateral Sclerosis and the marker protein is the tau protein; or the condition is Parkinson's Disease, Lewy body dementia or Alzheimer's Disease and the marker protein is alpha-synuclein (Column 2, Lines 44-65; emphasis added). In the method of the invention, macrophage cells are lysed and prepared for protein analysis; the cell lysate is mixed with monoclonal antibodies capable of binding fragments of the Aβ protein wherein exemplary antibodies are 6E10, 4G8 and 11A50-B10 which immune-precipitate Aβ fragments 1-16, Aβ fragments 17-24 and Aβ fragments of 1-40 while, in alternative embodiments, a different panel of antibodies, specific for other fragments, may be used (Column 8, Lines 23-43). Johnsen also discloses a diagnostic kit, wherein antibodies known in the art such as those detailed above may be used or further antibodies can be identified as is explained in the flow chart in Figure 9 in relation to antibodies to the Aβ protein (Columns 11-13). A suitable patient sample is obtained by extracting a cerebral spinal fluid sample by a lumbar puncture and the activated macrophages from the sample are extracted by binding of labelled antibodies to suitable cell markers (e.g., CD14 and CD16) in the patient sample and sorting of the cells by FACS wherein the isolated macrophages are then cultivated (box 11) and are encouraged to phagocytosis by challenging with the Aβ protein in vitro (box 12) (Id.). The cultivated macrophages are then lysed and digested fragments of the Aβ protein are extracted and immunoprecipitated (box 13) after which the Aβ fragments may, themselves, be used to immunize host animals (such as rabbits) in order to produce antibodies specific for the Aβ protein fragments on a small-scale (box 14) or, for larger scale production of antibodies, the procedure continues with the identification of the digested Aβ protein fragments using tandem mass spectrometry (e.g., electrospray-Q-TOF or MALDI-TOF (box 15)) wherein once the sequences of the Aβ protein fragments have been identified, the fragments are synthesized, for example by recombinant expression in a host cell such as E. coli (box 16), and the synthesized Aβ protein fragments are then used to immunize host animals (usually rabbits) (box 17) which in tum produce antibodies (box 18) (Id.). Antibodies may be obtained from the host animals and included in the diagnostic kits, but preferably, monoclonal antibody-producing cells are produced, as is known in the art (e.g., by production of hybridoma cells) or, alternatively, the antibodies, or at least their complementarity determining regions, are sequenced and recombinantly expressed; whichever method of antibody production is selected, the antibodies are purified and included in the diagnostic kit (box 19) (Id.). Thus, Johnsen explicitly teaches detecting Aβ fragments (e.g., resulting from phagocytosis), which can be identified via methods detailed above and after which antibodies specific for said fragments can be produced/purified.
It is noted, however, that Johnsen does not explicitly teach detecting peptide fragments that comprise an N-terminal sequence of FAEDVG (i.e., instant SEQ ID NO: 1). This deficiency is remedied by the combination of Hamazaki, Fiala, Rosenthal, and Bardroff.
Hamazaki discloses a study aimed at finding proteinases responsible for the intracellular clearance of Aβ, wherein the authors purified the Aβ degrading proteinase from rat brain, and amino-terminal sequence analysis indicated the Aβ degrading proteinase was cathepsin D; purified cathepsin D hydrolyzed Aβ between Phe19 and Phe20 and the authors conclude that cathepsin D is likely to be involved in the intracellular clearance of aggregatable Aβ, since Aβ fragments with Phe20 at the amino-terminus have been reported to be secreted from several lines of cultured cells (Abstract). To show cathepsin D is able to degrade aggregatable full-length Aβ, Aβ1-42 was incubated with the proteinase purified from rat brain; Fig. 3 shows that cathepsin D hydrolyzes Aβ1-42 after Phe19 and Leu 34, producing Aβ1-19, Aβ20-34, and Aβ35-42 wherein about 80% of Aβ1-42 was hydrolyzed in 4 h (Page 141, Column 1, First Full Paragraph). The specific hydrolysis of Aβ1-42 between Phe19 and Phe20 by cathepsin D suggests that this endoproteinase contributes to the generation of Aβ-related peptides with Phe20 at the NH2-terminus which have been described to be secreted from several lines of cultured cells (Id.). It is specifically noted that the peptide fragment Aβ20-34 would have the sequence FAEDVGSNKGAIIGL, which is a peptide having an N-terminal sequence corresponding to instant SEQ ID NO: 1 (the sequence corresponding to instant SEQ ID NO: 1 is underlined in the peptide sequence).
Fiala teaches that observation suggest that phagocytosis of amyloid-β by macrophages is excellent in normal subject, but is deficient in Alzheimer’s disease (AD) patients; peripheral blood leukocytes are a superior model system for the investigation of innate immune dysfunction in AD (Abstract). An appreciation of the role of macrophages in the innate immune system has been gained over the last century, which has established them as crucial for defense against microbes and removal of cellular debris (Page 457, Column 1); macrophages of normal subjects, but not of some AD patients, phagocytize and degrade large amounts of Aβ (Page 458, Column 1, First Full Paragraph). The authors’ initial neuropathological study of AD and control brains in 2002 showed penetration of blood derived monocytes across brain microvessels, excessive engorgement of macrophages with Aβ and retention of these macrophages in the wall of congophilic vessels; there is increasing evidence in animal studies that macrophages penetrate across brain microvessels by disrupting the inter-endothelial ZO-1 protein domains and significantly infiltrate perivascular and parenchymal sites and partially clear neuritic plaques, wherein the density of macrophage infiltration of neuritic plaques is not inversely related to residual Aβ,as would be expected if AD macrophages were efficiently clearing Aβ (i.e., AD macrophages penetrate across brain microvessels, but are not efficiently clearing Aβ) (Page 459, Column 1, Specific Defects of the Innate Immune Response in AD). Fiala further indicates that the chronic presence of assembled forms of Aβ, such as fibrillar and oligomeric, may induce an alternative activation state or deactivated phenotype in CNS microglia, which then actually inhibit phagocytosis of Aβ; in AD patients the defect in Aβ phagocytosis is found in peripheral monocytes and macrophages, suggesting a global defect of innate immunity in AD (Page 459, Column 2, First Full Paragraph). Thus, Fiala indicates deficient phagocytosis and clearance of Aβ both in the periphery and in the CNS. However, neither of Hamazaki nor Fiala disclose antibodies for the detection of Aβ fragments with Phe20 at the amino-terminus (i.e., comprising N-terminal sequence FAEDVG). This deficiency is remedied by the combination of Rosenthal and Bardroff.
Rosenthal teaches monoclonal antibody 9TL and antibodies derived from 9TL directed against amyloid-beta peptide and methods of using same for diagnosing and treatment of Alzheimer's disease and Aβ peptide associated diseases (Abstract). Antibodies and polypeptides of the invention can be used in the detection, diagnosis and monitoring of Alzheimer's disease and other diseases associated with altered Aβ or βAPP expression, such as Down's syndrome, and AIDS; the method comprises contacting a specimen of a patient suspected of having altered Aβ or βAPP expression with an antibody of the invention and determining whether the level of Aβ or βAPP differs from that of a control or comparison specimen wherein, in some embodiments, serum level of Aβ is measured before and after administration of an anti-Aβ antibody and any increase of serum level of Aβ is assessed (Paragraph 0061). A "biological sample" encompasses a variety of sample types obtained from an individual and can be used in a diagnostic or monitoring assay; the definition encompasses blood and other liquid samples of biological origin (i.e., body fluid sample), solid tissue samples such as a biopsy specimen or tissue cultures or cells derived therefrom, and the progeny thereof and also includes samples that have been manipulated in any way after their procurement, such as by treatment with reagents, solubilization, or enrichment for certain components, such as proteins or polynucleotides, or embedding in a semi-solid or solid matrix for sectioning purposes and generally encompasses a clinical sample including: cells in culture, cell supernatants, cell lysates, serum, plasma, biological fluid, and tissue samples (Paragraph 0105; emphasis added). Detection generally involves contacting a biological sample with an antibody described herein that binds to Aβ1-40 and the formation of a complex between Aβ1-40 and an antibody (e.g., 9TL) which binds specifically to Aβ1-40 wherein the formation of such a complex can be in vitro or in vivo; any of a variety of known methods can be used for detection, including, but not limited to, immunoassay, using antibody that binds the polypeptide, e.g., by enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA) and the like and, in some embodiments, the antibody is detectably labeled (Paragraphs 0213-0214). Thus, Rosenthal teaches monoclonal antibodies (i.e., specific to one epitope/antigenic site) that can be used for the detection, diagnosis and monitoring of Alzheimer's disease and other diseases associated with altered Aβ or βAPP comprising contacting a biological sample (i.e., body fluid sample) from a patient with the antibodies and detecting subsequently formed complexes.
Bardroff teaches antibody molecules capable of specifically recognizing two regions of the β-A4 peptide, wherein the first region comprises the amino acid sequence ABFRHDSGY as shown in SEQ ID NO: 1 or a fragment thereof and wherein the second region comprises the amino acid sequence VHHQKLVFFAEDVG as shown in SEQ ID NO: 2 or a fragment thereof in addition to compositions, preferably pharmaceutical or diagnostic compositions, comprising the compounds of the invention as well as for specific uses of the antibody molecules (Abstract; emphasis added). The term "two regions of the β-A4 peptide" relates to two regions as defined by their amino acid sequences shown in SEQ ID NOs: 1 and 2, relating to the N-terminal amino acids 2 to 10 and to the central amino acids 12 to 25 of β-A4 peptide wherein the term "β-A4 peptide" in context of the invention relates to Aβ39, Aβ41, Aβ43, preferably to Aβ40 and Aβ42; it is of note that the term "two regions of the β-A4 peptide" also relates to an "epitope" and/or an "antigenic determinant" which comprises the above-defined two regions of the β-A4 peptide or parts thereof (Paragraph 0017). The "antibody molecules" of the invention are thought to comprise a simultaneous and independent dual specificity to (a) an amino acid stretch comprising amino acids 2 to 10 (or (a) part(s) thereof) of β-A4 and (b) an amino acid stretch comprising amino acids 12 to 25 (or (a) part(s) thereof) of β-A4 (SEQ ID NO. 27); fragments or parts of these stretches comprise at least two, more preferably at least three amino acids wherein preferred fragments or parts are in the first region/stretch of SEQ ID NO: 27 the amino acid sequences AEFRHD, EF, EFR, FR, EFRHDSG, EFRHD or HDSG and in the second region/stretch of SEQ ID NO: 27 the amino acid sequences HHQKL, LV, LVFFAE, VFFAEDVFFA, or FFAEDV and said fragments may also comprise additional amino acids (Paragraph 0018; emphasis added). The antibodies/antibody molecules of the invention, by simultaneously (for example in a structural/conformational epitope formed by the N-terminal and central region of β-A4 as described herein) and independently (for example in pepspot assays as documented in the appended experimental part) binding to the N-terminal and central epitopes, combine the properties of an N-terminal-specific antibody and a central epitope-specific antibody in a single molecule; the term "simultaneously and independently binding to the N-terminal and central/middle epitopes of β-A4" in context of the antibody molecules relates to the fact that the antibodies/antibody molecules described herein may detect and/or bind to both epitopes simultaneously, i.e. at the same time (for example on conformational/structural epitopes formed by the N-terminal epitope (or (a) part(s) thereof) and central epitopes (or (a) part(s) thereof) of β-A4) and that the same antibody molecules, however, are also capable of detecting/binding to each of the defined epitopes in an independent fashion, as inter alia, demonstrated in the pepspot analysis shown in the examples (Paragraph 0024; emphasis added). Thus, Bardroff teaches a dual-specific antibody molecule capable of independently detecting/binding two epitopes of β-A4, including the amino acid sequence VHHQKLVFFAEDVG and fragments thereof; preferred fragments include HHQKL, LV, LVFFAE, VFFAEDVFFA, or FFAEDV which can also include additional amino acids. Thus, one of ordinary skill in the art would recognize that the envisioned antibody molecules of Bardroff could bind/detect the FAEDVG fragment of the recited VHHQKLVFFAEDVG epitope, and thus could bind/detect peptides (i.e., fragments of β-A4) consisting of FAEDVG. Bardroff further teaches a preferred embodiment of the invention in which a composition of the present invention is a diagnostic composition further comprising, optionally, suitable means for detection wherein said diagnostic composition may comprise the antibody molecules of the present invention employed for the detection and/or quantification of APP and/or APP-processing products, like amyloid-β or for the detection and/or quantification of pathological and/or (genetically) modified APP-cleavage sides (Paragraphs 0075-0078). Bardroff teaches various labels which can be used according to methods known in the art, and that detection methods comprise, but are not limited to, autoradiography, fluorescence microscopy, direct and indirect enzymatic reactions, etc. including commonly used detection assays comprising radioisotopic or non-radioisotopic methods such as Western blotting, overlay-assays, RIA (Radioimmuno Assay) and IRMA (Immune Radioimmunometric Assay), EIA (Enzyme Immuno Assay), ELISA (Enzyme Linked Immuno SorbentAssay), FIA(Fluorescent Immuno Assay), and CUA (Chemioluminescent Immune Assay) (Paragraphs 0081-0083). Thus, Bardroff teaches that antibody molecules of the invention can be used in diagnostic methods which comprise detecting APP and/or APP-processing products such as amyloid-β (and fragments/epitopes thereof as detailed above). While Bardroff teaches that many other monoclonal antibodies have been generated by immunizing mice with Aβ-derived fragments, and antibodies recognizing the C-terminal end of Aβl-40 and Aβl-42 are widely used to distinguish and quantitate the corresponding Aβ peptides in biological fluids and tissues, Bardroff does not explicitly teach peptide detection using the antibody molecules of the invention in biological fluids, nor does Bardroff explicitly teach detecting Aβ peptides comprising an N-terminal sequence of FAEDVG.
Thus, it would have been prima facie obvious to one of ordinary skill in the art to develop a method for detecting peptides in a sample comprising (i) obtaining a body fluid sample from a patient and (ii) detecting the presence of a peptide having an N-terminal amino acid sequence FAEDVG (i.e., SEQ ID NO: 1). One of ordinary skill in the art would have been motivated modify the method of Johnsen, based on the teachings of Hamazaki, Fiala, Rosenthal, and Bardroff to arrive at a method of detecting such a peptide and would have had a reasonable expectation of success.
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
In the instant case, it is noted that:
(1) Johnsen indicates a need for detecting the early stages of AD, and more specifically discloses detecting Aβ fragments (e.g., resulting from phagocytosis), which can be identified via methods comprising: (i) providing a sample comprising macrophages obtained from the patient (e.g., encompasses blood and other liquid samples of biological origin, i.e., body fluid sample); and (ii) detecting the presence of the marker protein or fragments thereof in the macrophages, wherein the condition is Alzheimer's Disease and the marker protein is the Aβ peptide, wherein macrophage cells are lysed and prepared for protein analysis, the cell lysate is mixed with monoclonal antibodies capable of binding fragments of the Aβ protein for immunoprecipitation.
(2) Hamazaki and Fiala both discuss phagocytosis of Aβ and its consequences with regard to AD pathology, wherein Hamazaki specifically implicates cathepsin D in phagocytosis of Aβ and the production of peptide fragments comprising the instantly claimed N-terminal sequence FAEDVG while Fiala indicates compromised/inefficient phagocytosis in the pathology of AD wherein phagocytosis in both the CNS and the periphery are inefficient.
(3) Rosenthal and Bardroff are both directed to antibodies specific for various fragments of Aβ, disclose methods of producing antibodies against Aβ peptide fragments, and the subsequent use of such antibodies in therapeutic, diagnostic, and/or detection-based methods.
Thus, to one of ordinary skill in the art, it would have been obvious to develop a method for detecting peptides in a sample comprising (i) obtaining a body fluid sample from a patient and (ii) detecting the presence of a peptide having an N-terminal amino acid sequence FAEDVG (i.e., SEQ ID NO: 1) because (i) Johnsen identifies a need for earlier AD detection, and provides methods comprising obtaining patient samples and detecting marker peptides (i.e., detecting Aβ peptides for AD), (ii) Hamazaki specifically implicates cathepsin D in phagocytosis of Aβ and the production of peptide fragments comprising the instantly claimed N-terminal sequence FAEDVG and Fiala indicates compromised/inefficient phagocytosis in the pathology of AD wherein phagocytosis in both the CNS and the periphery are inefficient, and (iii) Rosenthal and Bardroff teach antibodies specific for various fragments of Aβ, disclose methods of producing antibodies against Aβ peptide fragments, and the subsequent use of such antibodies in therapeutic, diagnostic, and/or detection-based methods. Thus, taken together, one of ordinary skill in the art would have a reasonable expectation of, generally, detecting peptides in a sample comprising (i) obtaining a body fluid sample, and (ii) subsequently detecting a peptide having the N-terminal sequence corresponding to FAEDVG (i.e., instant SEQ ID NO: 1) in order to, for example, diagnose AD earlier.
With regard to claims 2-7, Johnsen teaches that the invention relates to a strategy of diagnosing and monitoring diseases in the central nervous system (CNS); the approach of the present invention studies the immune cells, such as macrophages/microglia, in samples of, for example, cerebrospinal fluid (CSF) and blood, and measures abnormal levels or the absence of intracellular disease-specific peptides or proteins wherein activation of the macrophage/microglia system and phagocytosis of disease specific peptides/proteins provides a novel diagnostic tool and enables the progress and efficacy of therapeutic interventions to be assessed (Page 9). Rosenthal teaches that a "biological sample" encompasses a variety of sample types obtained from an individual and can be used in a diagnostic or monitoring assay; the definition encompasses blood and other liquid samples of biological origin (i.e., body fluid sample), solid tissue samples such as a biopsy specimen or tissue cultures or cells derived therefrom, and the progeny thereof and also includes samples that have been manipulated in any way after their procurement, such as by treatment with reagents, solubilization, or enrichment for certain components, such as proteins or polynucleotides, or embedding in a semi-solid or solid matrix for sectioning purposes and generally encompasses a clinical sample including: cells in culture, cell supernatants, cell lysates, serum, plasma, biological fluid, and tissue samples (Paragraph 0105; emphasis added). Additionally, one of ordinary skill in the art would recognize that biological samples of Rosenthal and Johnsen (e.g., blood, plasma, serum, and CSF) would inherently comprise leucocytes and monocytes in addition to the explicitly recited macrophages/microglia of Johnsen. Furthermore, Fiala implicates macrophages in Aβ phagocytosis both in the CNS and the periphery (see entire document). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claim 8, Rosenthal teaches that antibodies and polypeptides of the invention can be used in the detection, diagnosis and monitoring of Alzheimer's disease and other diseases associated with altered Aβ or βAPP expression, such as Down's syndrome,
and AIDS; the method comprises contacting a specimen of a patient suspected of having altered Aβ or βAPP expression with an antibody of the invention and determining whether the level of Aβ or βAPP differs from that of a control or comparison specimen wherein, in some embodiments, serum level of Aβ is measured before and after administration of an anti-Aβ
antibody and any increase of serum level of Aβ is assessed (Paragraph 0061). Thus, Rosenthal suggests the use of Aβ-specific antibodies for detecting peptides/proteins for the purpose of monitoring treatment. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
Double Patenting - New
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
It is noted that the new grounds of rejection below are based on the previous rejections of record, wherein additional prior art is included to address Applicant’s arguments. The claim rejections over 19/109,894 are new.
Claims 1-8 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 9,625,474 (herein after referred to as “’474”; disclosure beyond the claims referred to as “Johnson” because the disclosure qualifies as prior art under 35 U.S.C. 102(e)) in view of the disclosure of US 9,625,474 (herein after referred to as "Johnsen"; the disclosure qualifies as prior art under 35 U.S.C. 102(e)), non-patent literature by Hideaki Hamazaki (FEBS Letters, 1996, 396, 139-142; herein after referred to as “Hamazaki”), non-patent literature by Fiala et. al. (Journal of Alzheimer’s Disease, 2007, 11, 457-463; herein after referred to as “Fiala”), US 2006/0057702 A1 (previously cited on PTO-892; herein after referred to as "Rosenthal"), and US 2005/0169925 A1 (previously cited on PTO-892; herein after referred to as "Bardroff").
Claim 1 of ‘474 is drawn to a method of detecting differential levels of fragments of phagocytosed amyloid-beta peptide in a sample obtained from a patient generally comprising the steps of: (i) obtaining a sample of CSF or blood from a patient and subjecting said sample to cell sorting to isolate activated macrophages; (ii) lysing said activated macrophages and immunoprecipitating any amyloid-beta fragments; and (iii) detecting the level of said amyloid-beta fragments. Claims 2-9 of ‘474 detail: cell sorting techniques; peptide detection techniques; additional markers and their associated diseases that could be detected; the detecting step is conducted with antibody or fragment thereof that specifically binds amyloid-beta peptide and an antibody or fragment thereof that specifically binds a macrophage; the CSF sample is obtained by lumbar puncture; the detecting step is conducted with antibody or fragment thereof that specifically binds to a fragment of amyloid-beta peptide; the detecting step is conducted with antibody or fragment thereof that specifically binds amyloid-beta peptide; and the method further comprises identifying a patient as having Alzheimer’s disease when there is an reduced level of amyloid-beta peptide fragments compared to a standard level, respectively. Thus, ‘474 is drawn to a method of detecting peptides derived from a body fluid sample wherein said peptides can be fragments of amyloid-beta. However, ‘474 does not explicitly disclose a method of detecting peptides wherein the peptide has an N-terminal amino acid sequence of instant SEQ ID NO: 1, a body fluid sample comprising monocytes, body fluid samples that are serum or plasma, or detecting peptides in conjunction with monitoring treatment efficacy. These deficiencies are remedied by Johnsen, Hamazaki, Fiala, Rosenthal, and Bardroff, whose teachings are detailed above.
Thus, it would have been prima facie obvious to one of ordinary skill in the art to develop a method for detecting peptides in a sample comprising (i) obtaining a body fluid sample from a patient and (ii) detecting the presence of a peptide having an N-terminal amino acid sequence FAEDVG (i.e., SEQ ID NO: 1). One of ordinary skill in the art would have been motivated modify the method of ‘474, based on the teachings of Johnsen, Hamazaki, Fiala, Rosenthal, and Bardroff to arrive at a method of detecting such a peptide and would have had a reasonable expectation of success.
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
In the instant case, it is noted that:
(1) Johnsen indicates a need for detecting the early stages of AD, and more specifically discloses detecting Aβ fragments (e.g., resulting from phagocytosis), which can be identified via methods comprising: (i) providing a sample comprising macrophages obtained from the patient (e.g., encompasses blood and other liquid samples of biological origin, i.e., body fluid sample); and (ii) detecting the presence of the marker protein or fragments thereof in the macrophages, wherein the condition is Alzheimer's Disease and the marker protein is the Aβ peptide, wherein macrophage cells are lysed and prepared for protein analysis, the cell lysate is mixed with monoclonal antibodies capable of binding fragments of the Aβ protein for immunoprecipitation.
(2) Hamazaki and Fiala both discuss phagocytosis of Aβ and its consequences with regard to AD pathology, wherein Hamazaki specifically implicates cathepsin D in phagocytosis of Aβ and the production of peptide fragments comprising the instantly claimed N-terminal sequence FAEDVG while Fiala indicates compromised/inefficient phagocytosis in the pathology of AD wherein phagocytosis in both the CNS and the periphery are inefficient.
(3) Rosenthal and Bardroff are both directed to antibodies specific for various fragments of Aβ, disclose methods of producing antibodies against Aβ peptide fragments, and the subsequent use of such antibodies in therapeutic, diagnostic, and/or detection-based methods.
Thus, to one of ordinary skill in the art, it would have been obvious to develop a method for detecting peptides in a sample comprising (i) obtaining a body fluid sample (e.g., blood, serum, plasma, and/or CSF) from a patient and (ii) detecting the presence of a peptide having an N-terminal amino acid sequence FAEDVG (i.e., SEQ ID NO: 1) by modifying the method of ‘474 because (i) Johnsen identifies a need for earlier AD detection, and provides methods comprising obtaining patient samples and detecting marker peptides (i.e., detecting Aβ peptides for AD), (ii) Hamazaki specifically implicates cathepsin D in phagocytosis of Aβ and the production of peptide fragments comprising the instantly claimed N-terminal sequence FAEDVG and Fiala indicates compromised/inefficient phagocytosis in the pathology of AD wherein phagocytosis in both the CNS and the periphery are inefficient, and (iii) Rosenthal and Bardroff teach antibodies specific for various fragments of Aβ, disclose methods of producing antibodies against Aβ peptide fragments, and the subsequent use of such antibodies in therapeutic, diagnostic, and/or detection-based methods. Thus, taken together, one of ordinary skill in the art would have a reasonable expectation of, generally, detecting peptides in a sample comprising (i) obtaining a body fluid sample, and (ii) subsequently detecting a peptide having the N-terminal sequence corresponding to FAEDVG (i.e., instant SEQ ID NO: 1) in order to, for example, diagnose AD earlier and/or monitor treatment efficacy.
Claims 1-8 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 and 8-10 of U.S. Patent No. 11,231,426 (herein after referred to as “’426”) in view of US 9,625,474 (herein after referred to as "Johnsen), non-patent literature by Hideaki Hamazaki (FEBS Letters, 1996, 396, 139-142; herein after referred to as “Hamazaki”), non-patent literature by Fiala et. al. (Journal of Alzheimer’s Disease, 2007, 11, 457-463; herein after referred to as “Fiala”), US 2006/0057702 A1 (previously cited on PTO-892; herein after referred to as "Rosenthal"), and US 2005/0169925 A1 (previously cited on PTO-892; herein after referred to as "Bardroff").
Claim 1 of ‘426 is drawn to a method of detecting peptides in a sample generally comprising the steps of: (i) obtaining a blood sample from a patient, said sample comprising a cell type selected from leucocytes, monocytes, peripheral blood macrophages, and activated macrophages from peripheral blood; (ii) detecting the presence of a peptide consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 4 and SEQ ID NO: 5 in a given cell type wherein he peptide has both N- and C-terminal truncations compared to Aβ42. Claims 2-5 of ‘426 detail specific cell types in said blood sample (claims 2-3), isolating said cell types (claim 4), specific isolated cell type (claim 5). Claims 8-10 are directed to a similar method which further comprises the step of isolating a given cell type prior to detecting peptides. Thus, ‘426 is drawn to a method of detecting peptides derived from a body fluid sample wherein said peptides can be fragments of amyloid-beta (i.e., reference SEQ ID NOs: 4 and 5). However, ‘426 does not explicitly disclose a method of detecting peptides wherein the peptide has an N-terminal amino acid sequence of instant SEQ ID NO: 1, body fluid samples that are serum, plasma or CSF, or detecting peptides in conjunction with monitoring treatment efficacy. These deficiencies are remedied by Johnsen, Hamazaki, Fiala, Rosenthal, and Bardroff, whose teachings are detailed above.
Thus, it would have been prima facie obvious to one of ordinary skill in the art to develop a method for detecting peptides in a sample comprising (i) obtaining a body fluid sample from a patient and (ii) detecting the presence of a peptide having an N-terminal amino acid sequence FAEDVG (i.e., SEQ ID NO: 1). One of ordinary skill in the art would have been motivated modify the method of ‘’426, based on the teachings of Johnsen, Hamazaki, Fiala, Rosenthal, and Bardroff to arrive at a method of detecting such a peptide and would have had a reasonable expectation of success.
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
In the instant case, it is noted that:
(1) Johnsen indicates a need for detecting the early stages of AD, and more specifically discloses detecting Aβ fragments (e.g., resulting from phagocytosis), which can be identified via methods comprising: (i) providing a sample comprising macrophages obtained from the patient (e.g., encompasses blood and other liquid samples of biological origin, i.e., body fluid sample); and (ii) detecting the presence of the marker protein or fragments thereof in the macrophages, wherein the condition is Alzheimer's Disease and the marker protein is the Aβ peptide, wherein macrophage cells are lysed and prepared for protein analysis, the cell lysate is mixed with monoclonal antibodies capable of binding fragments of the Aβ protein for immunoprecipitation.
(2) Hamazaki and Fiala both discuss phagocytosis of Aβ and its consequences with regard to AD pathology, wherein Hamazaki specifically implicates cathepsin D in phagocytosis of Aβ and the production of peptide fragments comprising the instantly claimed N-terminal sequence FAEDVG while Fiala indicates compromised/inefficient phagocytosis in the pathology of AD wherein phagocytosis in both the CNS and the periphery are inefficient.
(3) Rosenthal and Bardroff are both directed to antibodies specific for various fragments of Aβ, disclose methods of producing antibodies against Aβ peptide fragments, and the subsequent use of such antibodies in therapeutic, diagnostic, and/or detection-based methods.
Thus, to one of ordinary skill in the art, it would have been obvious to develop a method for detecting peptides in a sample comprising (i) obtaining a body fluid sample (e.g., blood, serum, plasma, and/or CSF) from a patient and (ii) detecting the presence of a peptide having an N-terminal amino acid sequence FAEDVG (i.e., SEQ ID NO: 1) by modifying the method of ‘426 because (i) Johnsen identifies a need for earlier AD detection, and provides methods comprising obtaining patient samples and detecting marker peptides (i.e., detecting Aβ peptides for AD), (ii) Hamazaki specifically implicates cathepsin D in phagocytosis of Aβ and the production of peptide fragments comprising the instantly claimed N-terminal sequence FAEDVG and Fiala indicates compromised/inefficient phagocytosis in the pathology of AD wherein phagocytosis in both the CNS and the periphery are inefficient, and (iii) Rosenthal and Bardroff teach antibodies specific for various fragments of Aβ, disclose methods of producing antibodies against Aβ peptide fragments, and the subsequent use of such antibodies in therapeutic, diagnostic, and/or detection-based methods. Thus, taken together, one of ordinary skill in the art would have a reasonable expectation of, generally, detecting peptides in a sample comprising (i) obtaining a body fluid sample, and (ii) subsequently detecting a peptide having the N-terminal sequence corresponding to FAEDVG (i.e., instant SEQ ID NO: 1) in order to, for example, diagnose AD earlier and/or monitor treatment efficacy.
Claims 1-8 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 11,988,677 (herein after referred to as “’677”) in view of US 9,625,474 (herein after referred to as "Johnsen), non-patent literature by Hideaki Hamazaki (FEBS Letters, 1996, 396, 139-142; herein after referred to as “Hamazaki”), non-patent literature by Fiala et. al. (Journal of Alzheimer’s Disease, 2007, 11, 457-463; herein after referred to as “Fiala”), US 2006/0057702 A1 (previously cited on PTO-892; herein after referred to as "Rosenthal"), and US 2005/0169925 A1 (previously cited on PTO-892; herein after referred to as "Bardroff").
Claim 1 of ‘677 is drawn to a method of detecting peptides in a sample generally comprising the steps of: (i) obtaining a body fluid sample from a patient; (ii) detecting the presence of a peptide consisting of an amino acid sequence corresponding to SEQ ID NO: 5. Claims 2-8 of ‘677 detail specific cell types in said body fluid sample and/or what body fluid the sample originated from (claims 2-7), and that the detecting is performed in conjunction with monitoring efficacy of a treatment (claim 8). Thus, ‘667 is drawn to a method of detecting peptides derived from a body fluid sample wherein said peptides can be fragments of amyloid-beta (i.e., reference SEQ ID NOs: 5) as well as limitations regarding the body fluid samples and further monitoring treatment efficacy. However, ‘426 does not explicitly disclose a method of detecting peptides wherein the peptide has an N-terminal amino acid sequence of instant SEQ ID NO: 1. This deficiencies are remedied by Johnson, Hamazaki, Fiala, Rosenthal, and Bardroff, whose teachings are detailed above.
Thus, it would have been prima facie obvious to one of ordinary skill in the art to develop a method for detecting peptides in a sample comprising (i) obtaining a body fluid sample from a patient and (ii) detecting the presence of a peptide having an N-terminal amino acid sequence FAEDVG (i.e., SEQ ID NO: 1). One of ordinary skill in the art would have been motivated modify the method of ‘677, based on the teachings of Johnsen, Hamazaki, Fiala, Rosenthal, and Bardroff to arrive at a method of detecting such a peptide and would have had a reasonable expectation of success.
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
In the instant case, it is noted that:
(1) Johnsen indicates a need for detecting the early stages of AD, and more specifically discloses detecting Aβ fragments (e.g., resulting from phagocytosis), which can be identified via methods comprising: (i) providing a sample comprising macrophages obtained from the patient (e.g., encompasses blood and other liquid samples of biological origin, i.e., body fluid sample); and (ii) detecting the presence of the marker protein or fragments thereof in the macrophages, wherein the condition is Alzheimer's Disease and the marker protein is the Aβ peptide, wherein macrophage cells are lysed and prepared for protein analysis, the cell lysate is mixed with monoclonal antibodies capable of binding fragments of the Aβ protein for immunoprecipitation.
(2) Hamazaki and Fiala both discuss phagocytosis of Aβ and its consequences with regard to AD pathology, wherein Hamazaki specifically implicates cathepsin D in phagocytosis of Aβ and the production of peptide fragments comprising the instantly claimed N-terminal sequence FAEDVG while Fiala indicates compromised/inefficient phagocytosis in the pathology of AD wherein phagocytosis in both the CNS and the periphery are inefficient.
(3) Rosenthal and Bardroff are both directed to antibodies specific for various fragments of Aβ, disclose methods of producing antibodies against Aβ peptide fragments, and the subsequent use of such antibodies in therapeutic, diagnostic, and/or detection-based methods.
Thus, to one of ordinary skill in the art, it would have been obvious to develop a method for detecting peptides in a sample comprising (i) obtaining a body fluid sample (e.g., blood, serum, plasma, and/or CSF) from a patient and (ii) detecting the presence of a peptide having an N-terminal amino acid sequence FAEDVG (i.e., SEQ ID NO: 1) by modifying the method of ‘677 because (i) Johnsen identifies a need for earlier AD detection, and provides methods comprising obtaining patient samples and detecting marker peptides (i.e., detecting Aβ peptides for AD), (ii) Hamazaki specifically implicates cathepsin D in phagocytosis of Aβ and the production of peptide fragments comprising the instantly claimed N-terminal sequence FAEDVG and Fiala indicates compromised/inefficient phagocytosis in the pathology of AD wherein phagocytosis in both the CNS and the periphery are inefficient, and (iii) Rosenthal and Bardroff teach antibodies specific for various fragments of Aβ, disclose methods of producing antibodies against Aβ peptide fragments, and the subsequent use of such antibodies in therapeutic, diagnostic, and/or detection-based methods. Thus, taken together, one of ordinary skill in the art would have a reasonable expectation of, generally, detecting peptides in a sample comprising (i) obtaining a body fluid sample, and (ii) subsequently detecting a peptide having the N-terminal sequence corresponding to FAEDVG (i.e., instant SEQ ID NO: 1) in order to, for example, diagnose AD earlier and/or monitor treatment efficacy.
This is a provisional nonstatutory double patenting rejection.
Claims 1-8 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4-5, 9, 11, 13-15, 22, and 26-27 of copending Application No. 18/549,388 (herein after referred to as “’388”) in view of US 9,625,474 (herein after referred to as "Johnsen), non-patent literature by Hideaki Hamazaki (FEBS Letters, 1996, 396, 139-142; herein after referred to as “Hamazaki”), non-patent literature by Fiala et. al. (Journal of Alzheimer’s Disease, 2007, 11, 457-463; herein after referred to as “Fiala”), US 2006/0057702 A1 (previously cited on PTO-892; herein after referred to as "Rosenthal"), and US 2005/0169925 A1 (previously cited on PTO-892; herein after referred to as "Bardroff").
Claim 1 of ‘388 is drawn to an ex vivo method of determining the effect of an agent on catalysis by a Monocyte Phagocyte System (MPS) cell of a disease marker product and/or at least one fragment thereof associated with neurodegeneration and/or inflammatory activation, wherein said method comprises: (i) maintaining a sample of MPS cells under conditions in which the MPS cells remain alive; (ii) exposing the sample of MPS cells to an agent and a disease marker product, to permit phagocytosis of the disease marker product by the MPS cells; (iii) detecting the intracellular amount of the disease marker product and/or at least one fragment thereof in the sample of MPS cells; and (iv) comparing the intracellular amount of the disease marker product and/or the at least one fragment thereof to an intracellular amount of the same disease marker product and/or at least one fragment thereof measured in control MPS cells in the absence of the agent, wherein the effect of the agent on catalysis by MPS cells of the disease marker product and/or at least one fragment thereof is determined by the result of the comparison of step (iv), and wherein, when the disease marker product is Aβ1-42 (SEQ ID NO: 1) or Aβ1-40 (SEQ ID NO: 2), step (iii) comprises detecting the intracellular amount of a fragment of Aβ1-40 (SEQ ID NO: 2) or a fragment of Aβ1-42 (SEQ ID NO: 1) comprising residue 41 of Aβ1-42 (SEQ ID NO: 1) by detecting a region of the fragment comprising at least 4 amino acids including residue 21, residue 34 or residue 40 of Aβ1-42 (SEQ ID NO: 1) or Aβ1-40 (SEQ ID NO: 2) (emphasis added). It is specifically noted that MPC cells are obtained from human subjects via blood and/or CSF samples. Thus, the method of claim 1 is generally directed to detecting the amount of Aβ1-42, Aβ1-40, or fragments thereof (i.e., peptides) in a sample derived from a body fluid. Claims 2, 4-5, 9, 11, 13-15, 22, and 26-27 of ‘388 detail further limitations including MPS cell types (claim 2), how MPS cells are obtained (claims 4-5), that the disease marker or fragment thereof can be associated with Alzheimer’s disease (claim 9), marker fragment limitations (claims 11, and 13-14), the use of antibodies specific for various markers and marker fragments including an antibody specific for SEQ ID NO: 3 (100% match to instant SEQ ID NO: 1) (claim 15), uses of the method of claim 1 including monitoring treatment (claim 22), and kits comprising antibodies for markers or marker fragments (claims 26-27). However, ‘388 does not explicitly disclose a method of detecting peptides wherein the peptide has an N-terminal amino acid sequence of instant SEQ ID NO: 1 nor body fluid samples that are serum or plasma. These deficiencies are remedied by Johnson, Hamazaki, Fiala, Rosenthal, and Bardroff, whose teachings are detailed above.
Thus, it would have been prima facie obvious to one of ordinary skill in the art to develop a method for detecting peptides in a sample comprising (i) obtaining a body fluid sample from a patient and (ii) detecting the presence of a peptide having an N-terminal amino acid sequence FAEDVG (i.e., SEQ ID NO: 1). One of ordinary skill in the art would have been motivated modify the method of ‘388, based on the teachings of Johnsen, Hamazaki, Fiala, Rosenthal, and Bardroff to arrive at a method of detecting such a peptide and would have had a reasonable expectation of success.
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
In the instant case, it is noted that:
(1) Johnsen indicates a need for detecting the early stages of AD, and more specifically discloses detecting Aβ fragments (e.g., resulting from phagocytosis), which can be identified via methods comprising: (i) providing a sample comprising macrophages obtained from the patient (e.g., encompasses blood and other liquid samples of biological origin, i.e., body fluid sample); and (ii) detecting the presence of the marker protein or fragments thereof in the macrophages, wherein the condition is Alzheimer's Disease and the marker protein is the Aβ peptide, wherein macrophage cells are lysed and prepared for protein analysis, the cell lysate is mixed with monoclonal antibodies capable of binding fragments of the Aβ protein for immunoprecipitation.
(2) Hamazaki and Fiala both discuss phagocytosis of Aβ and its consequences with regard to AD pathology, wherein Hamazaki specifically implicates cathepsin D in phagocytosis of Aβ and the production of peptide fragments comprising the instantly claimed N-terminal sequence FAEDVG while Fiala indicates compromised/inefficient phagocytosis in the pathology of AD wherein phagocytosis in both the CNS and the periphery are inefficient.
(3) Rosenthal and Bardroff are both directed to antibodies specific for various fragments of Aβ, disclose methods of producing antibodies against Aβ peptide fragments, and the subsequent use of such antibodies in therapeutic, diagnostic, and/or detection-based methods.
Thus, to one of ordinary skill in the art, it would have been obvious to develop a method for detecting peptides in a sample comprising (i) obtaining a body fluid sample (e.g., blood, serum, plasma, and/or CSF) from a patient and (ii) detecting the presence of a peptide having an N-terminal amino acid sequence FAEDVG (i.e., SEQ ID NO: 1) by modifying the method of ‘388 because (i) Johnsen identifies a need for earlier AD detection, and provides methods comprising obtaining patient samples and detecting marker peptides (i.e., detecting Aβ peptides for AD), (ii) Hamazaki specifically implicates cathepsin D in phagocytosis of Aβ and the production of peptide fragments comprising the instantly claimed N-terminal sequence FAEDVG and Fiala indicates compromised/inefficient phagocytosis in the pathology of AD wherein phagocytosis in both the CNS and the periphery are inefficient, and (iii) Rosenthal and Bardroff teach antibodies specific for various fragments of Aβ, disclose methods of producing antibodies against Aβ peptide fragments, and the subsequent use of such antibodies in therapeutic, diagnostic, and/or detection-based methods. Thus, taken together, one of ordinary skill in the art would have a reasonable expectation of, generally, detecting peptides in a sample comprising (i) obtaining a body fluid sample, and (ii) subsequently detecting a peptide having the N-terminal sequence corresponding to FAEDVG (i.e., instant SEQ ID NO: 1) in order to, for example, diagnose AD earlier and/or monitor treatment efficacy.
Claims 1-8 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 14-32 of copending Application No. 19/109,894 (herein after referred to as “’894”) in view of US 9,625,474 (herein after referred to as "Johnsen), non-patent literature by Hideaki Hamazaki (FEBS Letters, 1996, 396, 139-142; herein after referred to as “Hamazaki”), non-patent literature by Fiala et. al. (Journal of Alzheimer’s Disease, 2007, 11, 457-463; herein after referred to as “Fiala”), US 2006/0057702 A1 (previously cited on PTO-892; herein after referred to as "Rosenthal"), and US 2005/0169925 A1 (previously cited on PTO-892; herein after referred to as "Bardroff").
Claims 14-15 of ‘894 are drawn to a method of detecting an Aβ protein fragment in a sample, generally comprising detecting the presence or quantity of an Aβ protein fragment in a biological sample obtained from an individual having or suspected of having amyloid angiopathy, amyloid-related imaging abnormalities (ARIA), or cerebral amyloid angiopathy (CAA), wherein the Aβ protein fragment is an Aβx-34 fragment or is a fragment of Aβ1-40, wherein claim 15 further comprises obtaining a biological sample from an individual having or suspected of having the above-recited conditions/abnormalities. Claim 16 of ‘894 is drawn to the biological sample being a blood sample or CSF. Claims 17-32 are drawn to specific Aβ fragments detected by way of the claimed methods. However, ‘894 does not explicitly disclose a method of detecting peptides wherein the peptide has an N-terminal amino acid sequence of instant SEQ ID NO: 1 nor body fluid samples that are serum or plasma. These deficiencies are remedied by Johnson, Hamazaki, Fiala, Rosenthal, and Bardroff, whose teachings are detailed above.
Thus, it would have been prima facie obvious to one of ordinary skill in the art to develop a method for detecting peptides in a sample comprising (i) obtaining a body fluid sample from a patient and (ii) detecting the presence of a peptide having an N-terminal amino acid sequence FAEDVG (i.e., SEQ ID NO: 1). One of ordinary skill in the art would have been motivated modify the method of ‘894, based on the teachings of Johnsen, Hamazaki, Fiala, Rosenthal, and Bardroff to arrive at a method of detecting such a peptide and would have had a reasonable expectation of success.
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
In the instant case, it is noted that:
(1) Johnsen indicates a need for detecting the early stages of AD, and more specifically discloses detecting Aβ fragments (e.g., resulting from phagocytosis), which can be identified via methods comprising: (i) providing a sample comprising macrophages obtained from the patient (e.g., encompasses blood and other liquid samples of biological origin, i.e., body fluid sample); and (ii) detecting the presence of the marker protein or fragments thereof in the macrophages, wherein the condition is Alzheimer's Disease and the marker protein is the Aβ peptide, wherein macrophage cells are lysed and prepared for protein analysis, the cell lysate is mixed with monoclonal antibodies capable of binding fragments of the Aβ protein for immunoprecipitation.
(2) Hamazaki and Fiala both discuss phagocytosis of Aβ and its consequences with regard to AD pathology, wherein Hamazaki specifically implicates cathepsin D in phagocytosis of Aβ and the production of peptide fragments comprising the instantly claimed N-terminal sequence FAEDVG while Fiala indicates compromised/inefficient phagocytosis in the pathology of AD wherein phagocytosis in both the CNS and the periphery are inefficient.
(3) Rosenthal and Bardroff are both directed to antibodies specific for various fragments of Aβ, disclose methods of producing antibodies against Aβ peptide fragments, and the subsequent use of such antibodies in therapeutic, diagnostic, and/or detection-based methods.
Thus, to one of ordinary skill in the art, it would have been obvious to develop a method for detecting peptides in a sample comprising (i) obtaining a body fluid sample (e.g., blood, serum, plasma, and/or CSF) from a patient and (ii) detecting the presence of a peptide having an N-terminal amino acid sequence FAEDVG (i.e., SEQ ID NO: 1) by modifying the method of ‘894 because (i) Johnsen identifies a need for earlier AD detection, and provides methods comprising obtaining patient samples and detecting marker peptides (i.e., detecting Aβ peptides for AD), (ii) Hamazaki specifically implicates cathepsin D in phagocytosis of Aβ and the production of peptide fragments comprising the instantly claimed N-terminal sequence FAEDVG and Fiala indicates compromised/inefficient phagocytosis in the pathology of AD wherein phagocytosis in both the CNS and the periphery are inefficient, and (iii) Rosenthal and Bardroff teach antibodies specific for various fragments of Aβ, disclose methods of producing antibodies against Aβ peptide fragments, and the subsequent use of such antibodies in therapeutic, diagnostic, and/or detection-based methods. Thus, taken together, one of ordinary skill in the art would have a reasonable expectation of, generally, detecting peptides in a sample comprising (i) obtaining a body fluid sample, and (ii) subsequently detecting a peptide having the N-terminal sequence corresponding to FAEDVG (i.e., instant SEQ ID NO: 1) in order to, for example, diagnose AD earlier and/or monitor treatment efficacy.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
On Pages 8-9 of Remarks (03/23/2026), Applicant argues the following with regard to the claim rejections under 35 U.S.C. 103(a), and subsequently the claim rejections under nonstatutory double patenting:
No reference in the combination-Bardroff, Rosenthal, or Johnsen, whether considered individually or together-teaches or suggests detecting a peptide having an N-terminal amino acid sequence FAEDVG; none of the references teaches or suggests detecting any peptide, whether six amino acids or longer, that has the N-terminal amino acid sequence FAEDVG, i.e., that starts at position 20 of Aβ1-42.
The assertion that SEQ ID NO: 1 "is a phagocytosis product of Aβ, which whether disclosed in the prior art or not would inherently be present and detectable in the method disclosed by Johnson [sic]." (Office Action, p. 6.) is unsupported; Applicant argues that this inherency argument fails because the Examiner has not established that a peptide having an N-terminal amino acid sequence FAEDVG, i.e., a peptide with an N-terminal boundary at position 20 of Aβ1-42 is necessarily produced during Aβ phagocytosis.
Even assuming, arguendo, that a peptide having an N-terminal amino acid sequence FAEDVG were somehow within the "scope" of Bardroff's broader disclosure, the Examiner has not established why a person of ordinary skill in the art would have been motivated to detect a peptide having an N-terminal boundary at position 20 of Aβ1-42 in a body fluid sample.
Applicant’s arguments with respect to claim(s) 1-8 have been considered but are moot because the new ground of rejections (under 35 U.S.C. 103(a) and nonstatutory double patenting) rely on a new combination of prior art references, wherein the additionally cited prior art references of Hamazaki and Fiala remedy the argued deficiencies regarding the instantly claimed Aβ peptide fragment(s). Furthermore, the teachings of the previously cited prior art have been more clearly presented such that the motivation for one of ordinary skill in the art to arrive at the instantly claimed method is more clearly presented.
Conclusion
Claims 1-8 are pending. Claims 1-8 are rejected. No claims are allowed.
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/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
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