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.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 11/12/2025 has been entered.
Withdrawn Rejections
The rejections of the claims under 101 are withdrawn in response to the amendments.
The rejections of the claims under 103 are withdrawn in response to the amendments, however, new grounds of rejection are set forth below.
Status of the Claims
Claims 1, 3-8, 10-11 and 13-21 are pending; claim 1 is amended; claims 2, 9 and 12 are canceled; claims 1, 3-8, 10-11 and 13-21 are examined below.
Priority
The present application was filed on 08/27/2021 and is a continuation of PCT/CN2020/085224, filed 04/17/2020. Acknowledgment is also made of applicant's claim for foreign priority under 35 U.S.C. 119(a)-(d) to Application No. 202010039229.1, filed on 1/15/2020 in China.
The certified copy has been filed in parent Application No. PCT/CN2020/085224, filed on 04/17/2020.
Claim Interpretation
35 USC § 112(f)
The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The following is a quotation of pre-AIA 35 U.S.C. 112, sixth paragraph:
An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. The broadest reasonable interpretation of a claim element (also commonly referred to as a claim limitation) is limited by the description in the specification when 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is invoked.
As explained in MPEP § 2181, subsection I, claim limitations that meet the following three-prong test will be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph:
(A) the claim limitation uses the term “means” or “step” or a term used as a substitute for “means” that is a generic placeholder (also called a nonce term or a non-structural term having no specific structural meaning) for performing the claimed function;
(B) the term “means” or “step” or the generic placeholder is modified by functional language, typically, but not always linked by the transition word “for” (e.g., “means for”) or another linking word or phrase, such as “configured to” or “so that”; and
(C) the term “means” or “step” or the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.
Use of the word “means” (or “step”) in a claim with functional language creates a rebuttable presumption that the claim limitation is to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites sufficient structure, material, or acts to entirely perform the recited function.
Absence of the word “means” (or “step”) in a claim creates a rebuttable presumption that the claim limitation is not to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is not interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites function without reciting sufficient structure, material or acts to entirely perform the recited function.
Claim limitations in this application that use the word “means” (or “step”) are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action. Conversely, claim limitations in this application that do not use the word “means” (or “step”) are not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action.
This application includes one or more claim limitations that do not use the word “means,” but are nonetheless being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, because the claim limitation(s) uses a generic placeholder that is coupled with functional language without reciting sufficient structure to perform the recited function and the generic placeholder is not preceded by a structural modifier. Such claim limitation(s) is/are: "the combination being configured to detect Alzheimer's disease with an overall sensitivity greater than 85 % and an overall specificity greater than 88 %" in claim 1.
The “combination” is considered a generic placeholder.
The generic placeholder is modified by functional language, “being configured to”.
The generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function “detect Alzheimer's disease with an overall sensitivity greater than 85 % and an overall specificity greater than 88 %”.
Because this/these claim limitation(s) is/are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, it/they is/are being interpreted to cover the corresponding structure described in the specification as performing the claimed function, and equivalents thereof.
If applicant does not intend to have this/these limitation(s) interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, applicant may: (1) amend the claim limitation(s) to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph (e.g., by reciting sufficient structure to perform the claimed function); or (2) present a sufficient showing that the claim limitation(s) recite(s) sufficient structure to perform the claimed function so as to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 3-8, 10-11 and 13-21 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
The claims recite “[a] protein antigen combination, comprising at least two protein fragments selected from the group consisting of: a microtubule associated protein tau (MAPT) fragment shown in SEQ ID NO:l, an Adenosine Deaminase RNA Specific Bl (ADARBI) fragment shown in SEQ ID NO:2, a protein p21 (WAFI/CIPI) (P21) fragment shown in SEQ ID NO:4, a DnaJ (Hsp40) homolog subfamily C member 8 (DNAJC8) fragment shown in SEQ ID NO:6, a receptor for advanced glycation endproducts (RAGE) fragment shown in SEQ ID NO:7, an additional sex combs-like protein I (ASXLI) fragment shown in SEQ ID NO:8, and a JMJD2D histone demethylase (JMJD2D) fragment shown in SEQ ID NO:9, the combination being configured to detect Alzheimer's disease with an overall sensitivity greater than 85 % and an overall specificity greater than 88 %...”.
The claims require a combination of at least two members of a group of 7 different protein fragments that are configured to detect Alzheimer's disease with an overall sensitivity greater than 85 % and an overall specificity greater than 88 %. Therefore, the number of combination of proteins claimed encompasses 27=128 – 8 = 120 (total number of possible subsets excluding the empty set and each item individually). However, the specification only discloses 10 combinations (see Table 7 pages 25-26) which is not considered sufficient support to show possession of the 120 combinations claimed. A person having ordinary skill in the art cannot envision the structure of the 120 combinations of proteins claimed capable of performing the claimed function (to detect Alzheimer's disease with an overall sensitivity greater than 85 % and an overall specificity greater than 88 %). Furthermore, from the 10 combinations disclosed, some fail to show an overall sensitivity greater than 85 % (see for example the sensitivity of “Candidate group 9” and “Candidate group 10” Table 8 page 29). Therefore, given the lack of written description support for “the combination being configured to detect Alzheimer's disease with an overall sensitivity greater than 85 % and an overall specificity greater than 88 %”, a person having ordinary skill in the art would question whether Applicant , had possession of the claimed invention.
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 1, 3-8, 10-11 and 13-21 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 limitation “the combination being configured to detect Alzheimer's disease with an overall sensitivity greater than 85 % and an overall specificity greater than 88 %,” invokes 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. However, the written description fails to disclose the corresponding structure, material, or acts for performing the entire claimed function and to clearly link the structure, material, or acts to the function.
The specification fails to provide sufficient structure to “the combination” claimed for detecting Alzheimer’s disease “with an overall sensitivity greater than 85 % and an overall specificity greater than 88 %”. Although the specification discloses 10 combinations (see Table 7 pages 25-26), some of the disclosed sensitivities are below the 85% claimed (see for example the sensitivity of “Candidate group 9” and “Candidate group 10” Table 8 page 29). The protein combination claimed encompasses such a large number of possible combinations that a person having ordinary skill in the art cannot visualize the corresponding structure that detects Alzheimer’s disease “with an overall sensitivity greater than 85 % and an overall specificity greater than 88 %”.
Therefore, the claim is indefinite and is rejected under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph.
Applicant may:
(a) Amend the claim so that the claim limitation will no longer be interpreted as a limitation under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph;
(b) Amend the written description of the specification such that it expressly recites what structure, material, or acts perform the entire claimed function, without introducing any new matter (35 U.S.C. 132(a)); or
(c) Amend the written description of the specification such that it clearly links the structure, material, or acts disclosed therein to the function recited in the claim, without introducing any new matter (35 U.S.C. 132(a)).
If applicant is of the opinion that the written description of the specification already implicitly or inherently discloses the corresponding structure, material, or acts and clearly links them to the function so that one of ordinary skill in the art would recognize what structure, material, or acts perform the claimed function, applicant should clarify the record by either:
(a) Amending the written description of the specification such that it expressly recites the corresponding structure, material, or acts for performing the claimed function and clearly links or associates the structure, material, or acts to the claimed function, without introducing any new matter (35 U.S.C. 132(a)); or
(b) Stating on the record what the corresponding structure, material, or acts, which are implicitly or inherently set forth in the written description of the specification, perform the claimed function. For more information, see 37 CFR 1.75(d) and MPEP §§ 608.01(o) and 2181.
Furthermore, claims 3 recites, “the combination further comprises…a dystroglycan (DAG) fragment”. However, it is not clear exactly what fragment is being claimed given that no sequence identifier is recited in claim 3. Claim 3 encompasses such a wide range in scope that a person having ordinary skill in the art would not be able to recognize the metes and bounds of the claim. Similarly claim 16, dependent of claim 3, is unclear. Claim 16 recites “the DAG fragment” but given that no sequence identifier is recited a person having ordinary skill in the art would not be able to recognize the metes and bounds of the claim.
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.
Claim(s) 1, 3, 10-11, 13-15, 19 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Cao and Sun (CN 109738653 A)-Cite No. 2 of IDS filed 8/27/2021 as evidenced by the National Library of Medicine (retrieved online https://www.ncbi.nlm.nih.gov/nuccore/NM_002156.5 on 2/28/2025)-Cite No. W of PTO892 3/19/2025, NLM (retrieved online https://www.ncbi.nlm.nih.gov/nuccore/NM_015338.5 on 2/24/2025) -Cite No. W of PTO892 3/19/2025, NLM (retrieved online https://www.ncbi.nlm.nih.gov/nuccore/NM_014280 on 2/11/2026), NLM (retrieved online https://www.ncbi.nlm.nih.gov/nuccore/NM_001136.5 on 2/11/2026), NLM (retrieved online https://www.ncbi.nlm.nih.gov/nuccore/NM_002156.5 on 2/12/2026), NLM (retrieved online https://www.ncbi.nlm.nih.gov/nuccore/NM_016835.4 on 2/11/2026), NLM (retrieved online https://www.ncbi.nlm.nih.gov/nuccore/NM_001112.4 on 2/11/2026), NLM (retrieved online https://www.ncbi.nlm.nih.gov/nuccore/NM_000389 on 2/11/2026), NLM (retrieved online https://www.ncbi.nlm.nih.gov/nuccore/NM_018039.3 on 2/11/2026).
Although the reference by Cao and Sun (CN 109738653 A) was published within the grace period of the foreign priority application (CN202010039229.1 effectively filed on 01/15/2020) and includes the inventor, Liqin Cao, in the present application, this reference does not clearly fall into the 102(b)(1)(A) exception because the foreign patent application publication includes another author not listed in the present application, specifically: Supeng Sun. It is not clear from the record that the 102(b)(1)(A) exception applies.
Regarding claims 1, 3, 13-15, 19 and 21, Cao and Sun teach a protein antigen combination, comprising at least two protein fragments selected from the group consisting of: a microtubule associated protein tau (MAPT) fragment shown in SEQ ID NO:1, an ADARB1 (human) recombinant protein (ADARB1) fragment shown in SEQ ID NO:2, a protein p21^(WAF1/CIP1) (P21) fragment shown in SEQ ID NO:4, a DnaJ (Hsp40) homolog subfamily C member 8 (DNAJC8) fragment show in in SEQ ID NO:6, a receptor for advanced glycation endproducts (RAGE) fragment shown in SEQ ID NO:7, an additional sex combs-like protein 1 (ASXL1) fragment shown in SEQ ID NO:8, and a JMJD2D histone demethylase (JMJD2D) fragment shown in SEQ ID NO:9; wherein the protein antigen combination further comprises a heat shock protein 60 (HSP60) shown in SEQ ID NO:3, the MAPT protein fragment shown in SEQ ID NO:l, and the ADARBl protein fragment shown in SEQ ID NO:2; the DNAJC8 protein fragment shown in SEQ ID NO:6, the RAGE protein fragment shown in SEQ ID NO:7, and the ASXLl protein fragment shown in SEQ ID NO:8; and the ADARB1 protein fragment shown in SEQ ID NO:2, the RAGE protein fragment shown in SEQ ID NO:7, and the ASXLl protein fragment shown in SEQ ID NO:8 (“a method for detecting Alzheimer's disease in serum antibody kit, said kit comprising the antigen protein combination, combination of the antigen protein comprises at least four protein, said protein is selected from … RAGE… MAPT… DNAJC8…HSP60, ADARB1, ASXL1,… P21” Abstract, “The desired recombinant antigen protein fragment was prepared by PCR” page 22 para. 10, “Example 1 Protein Screening as an Antigen of Autoantibodies Through literature search, 50 known proteins related to Alzheimer's disease were selected, as shown in Table 2. Table 2. Sequence of the protein to be tested… DNAJC8 NM_014280… RAGE NM_001136.5…HSP60 NM_002156.5…MAPT NM_016835.4… ADARBl NM_001112.4… ASXLl NM_015338.5… P21 NM_000389… JMJD2D NM_018039.3” see Table 2). Note that as evidenced by the National Library of Medicine (NLM), the ID numbers taught by Cao and Sun correspond to sequences that are 100% matched to the sequences claimed in the instant invention. Regarding the recitation of: “the combination being configured to detect Alzheimer's disease with an overall sensitivity greater than 85 % and an overall specificity greater than 88 %,” Applicant is reminded that the subject matter of a properly construed claim is defined by the terms that limit the scope of the claim when given their broadest reasonable interpretation. It is this subject matter that must be examined. As a general matter, grammar and the plain meaning of terms as understood by one having ordinary skill in the art used in a claim will dictate whether, and to what extent, the language limits the claim scope. See MPEP § 2111.01 for more information on the plain meaning of claim language. Language that suggests or makes a feature or step optional but does not require that feature or step does not limit the scope of a claim under the broadest reasonable claim interpretation. Here, it appears that “the combination being configured to detect Alzheimer's disease with an overall sensitivity greater than 85 % and an overall specificity greater than 88 %,” fails to impart any structural limitation to the protein antigen combination claimed; furthermore the combination itself, i.e. the specific sequences of the fragments are reasonably considered to be inherently configured to detect Alzheimer's disease with an overall sensitivity greater than 85 % and an overall specificity greater than 88 % as these protein fragments are indistinguishable from the protein fragments of the instant invention. Cao and Sun further teach wherein each protein fragment of the protein antigen combination is fused to a heterologous tag, wherein the heterologous tag comprises a HIS tag or a c-myc tag (“a suitable tag such as HIS, c-myc or the like is added upstream of the antigen coding sequence to form a fusion protein” page 22 para. 10). Cao and Sun further teach that Alzheimer’s disease is common and deadly in the elderly population, causing public health concerns and economic burden (“by the age of 80, the proportion has risen to more than 30%. The average survival of AD patients is estimated to be 10-15 years, which is the fourth leading cause of death in the elderly population…the total social and economic burden caused by Alzheimer's disease in China reached 167.74 billion US dollars…has caused growing public health problems” page 17 para. 3). Cao and Sun further teach that “early diagnosis of the disease is essential to prevent or delay the onset of the disease or the appearance of clinical symptoms” (page 17 para. 4).
Cao and Sun fail to teach the protein antigen combination of claims 1, 3, 13-15, 19 and 21 in a manner consistent with anticipation, i.e., there is some picking and choosing involved to arrive at the protein antigen combination claimed from the list of proteins of Table 2 of Cao and Sun.
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 tried picking the combination of protein fragments claimed from the finite list of protein fragments taught by Cao and Sun in Table 2 because Cao and Sun teach that the protein fragments are related to Alzheimer's disease, which is a common and deadly disease and a current public health concern. One would have been motivated to try making such combinations because Cao and Sun teach that early diagnosis of the disease is essential to prevent or delay the onset of the disease or the appearance of clinical symptoms and suggests using the proteins for screening Alzheimer’s disease autoantibodies. A person having ordinary skill in the art would have had a reasonable expectation of success because Cao and Sun teach the National Library of Medicine identification number of each protein.
Regarding claim 10, Cao and Sun further teach a kit for detecting Alzheimer' s disease, comprising: the protein antigen combination of claim 1, purified and prepared for detecting autoantibodies against at least one of the protein fragments in a biological sample; a labeled anti-human antibody that binds to the autoantibodies; and a chromogenic agent that changes an absorbance of light at a predetermined wavelength in a test sample containing the protein antigen combination, the autoantibodies and the labeled anti-human antibody (Abstract, claim 3 of Cao and Sun). Cao and Sun disclose “purifying by Ni column” a protein antigen composition (specific embodiment), and using “2) sheep anti-human immunoglobulin marked by horseradish peroxidase”, as well as “TMB developer… at 450nm wavelength plate” (specific implementation methods) to detect Alzheimer’s disease.
Regarding claim 11, Cao and Sun teach wherein the biological sample is serum (Abstract).
However, Applicant is reminded that claim scope is not limited by claim language that does not limit a claim to a particular structure. See MPEP 2111.04.With respect to claim 11, the recitation of the sample for the intended use or operating of the kit does not convey any clear structural limitations to the kit itself.
Claims 4-8, 16-18 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Cao and Sun as applied to claim 3 above, and further in view of Rouslahti et al. (US 11571485 B2) ("Rouslahti").
Regarding claims 4 and 16-17, Cao and Sun teach the protein antigen combination according to claim 3 as discussed above.
Cao and Sun further teach comprising the JMJD2D protein fragment shown in SEQ ID NO:9, and the P21 protein fragment shown in SEQ ID NO:4 (Table 2 of Cao and Sun)
Cao and Sun fail to teach a DAG fragment shown in SEQ ID NO:5.
Rouslahti teaches “peptides and antibodies for detecting changes in Alzheimer’s disease brain and methods of use thereof” (Title). Rouslahti further teaches that “the peptide has an amino acid sequence as set forth in SEQ ID NO: 102 (CDAGRKQKC; also herein referred to as “DAG”)” (para. 25). Note that SEQ ID NO: 102 (CDAGRKQKC) is 100% matched to SEQ ID NO:5 claimed.
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 Cao and Sun to include the DAG fragment shown in SEQ ID NO:5 taught by Rouslahti because Rouslahti teaches that this peptide detects changed in Alzheimer's disease brain and Cao and Sun are concerned with detecting Alzheimer's disease, a current health crisis. A person having ordinary skill in the art would have had a reasonable expectation of success because both Cao and Sun and Rouslahti are drawn to peptides related to Alzheimer’s disease.
Regarding claims 5-8, 18 and 20, Cao and Sun in view of Rouslahti teach the protein antigen combination according to claim 4 as discussed above.
Cao and Sun in view of Rouslahti further teach comprising the MAPT protein fragment shown in SEQ ID NO:l, the ADARBI protein fragment shown in SEQ ID NO:2, and the HSP60 protein having the sequence shown in SEQ ID NO:3; comprising the DNAJC8 protein fragment shown in SEQ ID NO:6, the RAGE protein fragment shown in SEQ ID NO:7, and the ASXLI protein fragment shown in SEQ ID NO:8; comprising the JMJD2D protein fragment shown in SEQ ID NO:9, the P21 protein fragment shown in SEQ ID NO:4, and the DAG fragment shown in SEQ ID NO:5; comprising: the MAPT protein fragment shown in SEQ ID NO:l, the HSP60 protein having the sequence shown in SEQ ID NO:3, and the DNAJC8 protein fragment shown in SEQ ID NO:6; the ADARBI protein fragment shown in SEQ ID NO:2, the RAGE protein fragment shown in SEQ ID NO:7, and the ASXLI protein fragment shown in SEQ ID NO:8; and (iii) the HSP60 protein having the sequence shown in SEQ ID NO:3, the RAGE protein fragment shown in SEQ ID NO:7, and the P21 protein fragment shown in SEQ ID NO: 4 (see Table 2 of Cao and Sun).
Claims 1, 10-11 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Nagele (US 2014/0364328 A1)-Cite No. A of PTO892 11/13/2024 as evidenced by the National Library of Medicine (NLM) (retrieved online https://www.ncbi.nlm.nih.gov/nuccore/NM_015833.1 on 2/12/2026), NLM (retrieved online https://www.ncbi.nlm.nih.gov/nuccore/BC033159.1 on 2/12/2026), NLM (retrieved online https://www.ncbi.nlm.nih.gov/nuccore/BC064984.1 on 2/12/2026), and NLM (retrieved online https://www.ncbi.nlm.nih.gov/nuccore/NM_018039.2 on 2/12/2026).
Regarding claims 1 and 21, Nagele teaches a protein antigen combination, comprising at least two protein fragments selected from the group consisting of an ADARB1 fragment show in SEQ ID NO:2, a protein p21, a DNAJC8 fragment shown in SEQ ID NO:6, an ASXL1 fragment shown in SEQ ID NO:8, and a JMJD2D fragment shown in SEQ ID NO:9 (“methods, compositions and kits for the detection of Parkinson' disease (PD) diagnostic biomarkers, for the diagnosis of PD, for the identification of a subject at risk for developing PD, and for the generation of patient-specific PD diagnostic biomarker profiles” Abstract, “NM_018039.2…JMJD2D…BC064984.1…ASXL1…p21…NM_0l5833.l…ADARB1…BC033159.1…DNAJC8” Table 1 pages 7-9 and 12). Note that as evidenced by the National Library of Medicine (NLM), the ID numbers taught by Nagele correspond to sequences that are 100% matched to the sequences claimed in the instant invention. Regarding the recitation of: “the combination being configured to detect Alzheimer's disease with an overall sensitivity greater than 85 % and an overall specificity greater than 88 %,” Applicant is reminded that the subject matter of a properly construed claim is defined by the terms that limit the scope of the claim when given their broadest reasonable interpretation. It is this subject matter that must be examined. As a general matter, grammar and the plain meaning of terms as understood by one having ordinary skill in the art used in a claim will dictate whether, and to what extent, the language limits the claim scope. See MPEP § 2111.01 for more information on the plain meaning of claim language. Language that suggests or makes a feature or step optional but does not require that feature or step does not limit the scope of a claim under the broadest reasonable claim interpretation. Here, it appears that “the combination being configured to detect Alzheimer's disease with an overall sensitivity greater than 85 % and an overall specificity greater than 88 %,” fails to impart any structural limitation to the protein antigen combination claimed; furthermore the combination itself is reasonably considered to be inherently configured to detect Alzheimer's disease with an overall sensitivity greater than 85 % and an overall specificity greater than 88 %. Nagele further suggests wherein each protein fragment of the protein antigen combination is fused to a heterologous tag, wherein the heterologous comprises a HIS tag or a c-myc tag (“The antigens may be purified from natural sources, or produced recombinantly or synthetically by methods known in the art, and may be in the form of fusion proteins” para. 22, “Covalent coupling methods provide a stable linkage and may be applied to a range of proteins. Biological capture methods utilizing a tag (e.g., hexahistidine/Ni-NTA or biotin/avidin) on the protein and a partner reagent immobilized on the surface of the substrate provide a stable linkage and bind the protein specifically and in reproducible orientation” para. 24). Note that although Nagele fails to use the language “fused to a heterologous tag”, the teaching that the antigens may be purified in the form of fusion proteins, together with the teaching of a hexahistidine/Ni-NTA tag suggests that the purification involves fusing a HIS tag, i.e. a heterologous tag, to the protein. Nagele further teaches that Parkinson’s disease is a common and serious disease “inflicting profound social and economic costs worldwide” (“It is the second most common neurodegenerative disorder after Alzheimer's disease…By the time a diagnosis is made, at least one-third of substantia nigra neurons and striatal dopaminergic fibers are already lost (Greffard et al. (2006) Arch Neural 63:584-588)” para. 2). Nagele further teaches that there is “widespread recognition that early detection facilitating early treatment helps to slow the progression of the disease, minimize symptoms, and improve the overall quality of life” (para. 4) and teaches the use of the protein antigens of Table 1 to identify autoantibodies of PD (“PD diagnostic biomarkers are defined herein as antibodies, including for example autoantibodies, that specifically bind to protein antigens and are diagnostic indicators that can be used to differentiate PD from control subjects without PD. The term "protein antigens" as used herein includes protein and peptide antigens. In one embodiment, protein antigens that have been identified as capable of being specifically bound by the PD diagnostic biomarkers are set forth in the following Table 1” para. 12).
Nagele fails to teach the protein antigen combination in a manner consistent with anticipation, i.e., there is some picking and choosing involved to arrive at the protein antigen combination claimed from the list of proteins of Table 1 of Nagele.
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 tried picking the combination of protein fragments claimed from the finite list of protein fragments taught by Nagele in Table 1 because Nagele teaches that the protein fragments are used to identify autoantibodies of Parkinson's disease (PD), which is a common and serious disease and a current public health concern. One would have been motivated to try making such combinations because Nagele teaches that early diagnosis of the disease is essential to prevent or delay the onset of the disease and improve the overall quality of life and suggests using the proteins for screening PD autoantibodies. A person having ordinary skill in the art would have had a reasonable expectation of success because Nagele teaches the National Library of Medicine identification number of each protein.
Regarding claim 10, Nagele teaches a kit for detecting Parkinson’s disease, comprising: the protein antigen combination of claim 1 (see above), “purified” (paragraph 26) and prepared for “detecting… autoantibodies” (paragraph 12) against at least one of the protein fragments in a biological sample (paragraphs 21-22); and a labeled anti-human antibody that binds to the autoantibodies; and a chromogenic agent that changes an absorbance of light at a predetermined wavelength (“anti-human IgG (H+L) conjugated to AlexaFluor 647” paragraphs 48-49) in a test sample containing the protein antigen combination, the autoantibodies and the labeled anti-human antibody (paragraph 21).
It is noted that the preamble of the claim indicates the kit is for detecting Alzheimer’s disease. Applicant is reminded that the normal purpose of a claim preamble is to recite the purpose or intended use of the claimed invention. Such statements merely define the context in which the invention operates and usually will not limit the scope of the claim (MPEP 2111.02 and DeGeorge v. Bernier, Fed. Cir. 1985, 226 USPQ 758, 761 n.3).
In the instant case, the statements in the preambles do not provide antecedent basis for terms in the bodies of the claims, and are not essential to understand the limitations or terms in the bodies of the claims. For these reasons, the preambles may be reasonably interpreted simply as a referring to possible intended uses of the claimed kits.
Furthermore, a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
In the present case, Nagele teaches a kit comprising a combination of protein as presently claimed, the kit capable of detecting autoantibodies to these markers (see as cited above). Therefore, Nagele would also necessarily be capable of being applied to detect autoantibodies to these proteins, even the presence of such are related to Alzheimer’s.
Regarding claim 11, similarly as discussed above, the particular sample which the kit is intended to be used on is specific to the intended use of the claimed kit (the sample is not a structural component of the kit itself). Nonetheless, it is noted that Nagele teaches wherein the biological sample is whole blood or serum (paragraph 20). As a result, it would be expected that the kit (combination of proteins as taught by Nagele) would similarly be capable of the intended use applied to samples as claimed.
Claims 3-4 are rejected under 35 U.S.C. 103 as being unpatentable over Nagele as applied to claim 1 above, and further in view of Rouslahti et al. (US 11571485 B2) ("Rouslahti").
Regarding claims 3-4, Nagele teaches the protein antigen combination according to claim 1 as discussed above.
Nagele fails to teach a DAG fragment shown in SEQ ID NO:5.
Rouslahti teaches “peptides and antibodies for detecting changes in Alzheimer’s disease brain and methods of use thereof” (Title). Rouslahti further teaches that “the peptide has an amino acid sequence as set forth in SEQ ID NO: 102 (CDAGRKQKC; also herein referred to as “DAG”)” (para. 25). Note that SEQ ID NO: 102 (CDAGRKQKC) is 100% matched to SEQ ID NO:5 claimed. Rouslahti also teaches that the peptide “DAG (SEQ ID NO: 102)… homed to cells in human…Parkinson's disease brain” (para. 165) and suggests the use of DAG as an imaging biomarker for Parkinson’s disease (“The fact that DAG homes to brain in animal models of Parkinson's disease, brain injury, and glioblastoma agrees with the published CTGF expression pattern and suggests that DAG has the potential for broad applicability in brain diseases. For example, imaging applications are envisioned, in which the differential diagnosis could be based on the pattern of accumulation of the DAG-guided contrast agent” para. 221).
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 Nagele to include the DAG fragment shown in SEQ ID NO:5 taught by Rouslahti because Rouslahti suggest that this peptide targets Parkinson's disease brain and Nagele is concerned with detecting PD, a current health crisis. A person having ordinary skill in the art would have had a reasonable expectation of success because both Nagele and Rouslahti are drawn to peptides related to PD.
Claims 5, 13-14 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Nagele in view of Rouslahti as applied to claims 3-4 above, and further in view of Papuc et al. (2015) PLOS ONE | DOI:10.1371/journal.pone.0115480 ("Papuc"), Valkirs et al. (US 20030109420 A1) -Cite No. C in PTO892 11/13/2024, Coleman et al. (WO/2006/020269) -Cite No. O in PTO892 3/19/2025 (hereinafter Coleman), Kronimus et al. PLOS ONE E 11(11): e0164953 doi:10.1371/journal.pone.0164953-Cite No. X of PTO892 11/13/2025 and Moe and Davidwitz (WO2010/021755) -Cite No. N in PTO892 11/13/2024.
Regarding claims 5, 13-14 and 18, Nagele in view of Rouslahti teach the combination of claims 3-4 as discussed above.
Nagele in view of Rouslahti fail to teach comprising the MAPT protein fragment shown in SEQ ID NO:1, and the HSP60 protein fragment shown in SEQ ID NO:3.
Papuc teaches “Humoral Response against Small Heat Shock Proteins in Parkinson’s Disease” (Title). Papuc teaches using HSP60 protein to detect “anti-HSP 60 autoantibodies…in serum of parkinsonian patients and healthy controls” (page 7 para. 4). Note that although Papuc did not detect a statistical significant difference in anti-HSP60 autoantibodies between PD patients and controls, Papuc still suggests that the Parkinson’s disease has an “inducing effect” in the humoral response (page 7 para. 4). Papuc further suggests using HSP60 “to delineate immune response typical for PD. This in turn could be potentially helpful to find the surrogate markers for this chronic neurodegenerative disorder” (page 7 para. 5).
Valkirs et al. teach methods for the diagnosis and evaluation, specifically early detection and differentiation, of a health condition based on sample analysis regarding the presence and amount of members of a panel of markers (Abstract). Valkirs et al. further teach combining a plurality of makers can “increase the predictive value of the analysis” in comparison to an analysis of individual markers (paragraph 17); and particularly the 'multimarker' strategy presents a benefit with regards to risk stratification (“there is a demonstrated benefit of using a multimarker strategy that incorporates different independent markers” paragraph 184).
Coleman teaches “biomarkers of neurodegenerative disease” (Title). Coleman further teaches that “[s]pecific examples of these biomarkers include, but are not limited to, HSP60” (paragraph 127). Coleman further teaches that “[t]he disclosed compositions can be used in a variety of ways as research tools. For example, the disclosed compositions, such as SEQ ID NOs: 1-257 can be used to study the effects of various therapies on a neurodegenerative disease The compositions can be used for example as targets in combinatorial chemistry protocols or other screening protocols to isolate molecules that possess desired functional properties related to a neurodegenerative disease (e.g., Alzheimer's and Parkinson's disease). The disclosed compositions can also be used diagnostic tools related to neurodegenerative diseases such as Alzheimer's and Parkinson's disease” (paragraphs 253-255). Note that SEQ ID NO:241 is 100% matched to SEQ ID NO:3 of the instant invention.
Kronimus et al. “Naturally Occurring Autoantibodies against Tau Protein Are Reduced in Parkinson's Disease Dementia” (Title). Kronimus et al. further teach MAPT is associated with Parkinson’s disease, namely that demented Parkinson’s disease patients (PDD) “had significantly decreased [naturally occurring autoantibodies] nAbs-tau serum levels compared to [non-demented Parkinson’s disease] PDND patients (p = 0.007)” (Abstract).
Moe and Davidwitz teach that “abnormal forms of tau are sufficient for neurodegeneration causing memory loss and other neurological deficits in multiple frontotemporal dementia and sporadic tauopathies…Parkinson disease” (paragraphs 108 and 109), and that “[i]n the process of disease tau protein becomes modified…oligomeric forms of tau are best associated with neuron loss” (Abstract). Furthermore, Moe and Davidwitz disclose the MAPT protein fragment as shown in SEQ ID No. 1 of the instant application in Example 6, teaching the resulting fragment when “tau oligomer cuts itself” (paragraph 123).
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 modify the teachings of Nagele in view of Rouslahti namely including HSP60, taught by Papuc, in the protein antigen combination, thereby arriving at the present claim, (i.e., to provide the combination of proteins together), because Valkirs et al. teach that combining makers can increase the predictive value of the analysis and both Nagele and Papuc teach protein antigen biomarkers of Parkinson’s disease. One would have been motivated to make such a modification in order to receive the expected benefit of diagnosing Parkinson's disease earlier, thereby slowing the progression of the disease, minimizing symptoms, and improving the overall quality of life as taught by Nagele, specifically combining the proteins together as a single product since such combination would allow for the use to detect the combination of autoantibodies, thereby increasing the predictive/diagnostic value of the product. A person having ordinary skill in the art would have had a reasonable expectation of success given that both Nagele and Papuc teach protein antigens for detecting Parkinson’s Disease.
It would have been further prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Nagele in view of Rouslahti, Papuc and Valkirs et al. to rely on HSP60 shown in SEQ ID NO:3 taught by Coleman because Coleman teaches that HSP60 shown in SEQ ID NO:3 is used to diagnose Parkinson's disease. Therefore, applying the HSP60 protein fragment shown in SEQ ID NO:3 taught by Coleman to the art-recognized technique of using HSP60 as a biomarker of Parkinson’s disease taught by both Papuc and Coleman would have been obvious to a person having ordinary skill in the art. One would have been motivated to make such a modification because Nagele teaches that diagnosing PD early can increase the quality of life of the patient. A person having ordinary skill in the art would have had a reasonable expectation of success because Coleman teaches SEQ ID NO:3 in the context of neurodegenerative diseases, i.e., Parkinson’s disease, and Nagele in view of Rouslahti, Papuc and Valkirs et al. teach protein antigen combinations for detecting Parkinson’s Disease.
It would have been further prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Nagele in view of Rouslahti, Papuc, Valkirs et al. and Coleman to include the MAPT protein taught by Kronimus et al. (i.e., to provide the combination of proteins together), thereby arriving at the instant claim, because Valkirs et al. teach that combining makers can increase the predictive value of the analysis and both Nagele and Kronimus et al. teach protein antigens to detect the related autoantibody makers shown to be associated with Parkinson’s disease. One would have been motivated to make such a modification in order to receive the expected benefit of diagnosing Parkinson's disease earlier, thereby slowing the progression of the disease, minimizing symptoms, and improving the overall quality of life as taught by Nagele, specifically combining the proteins together as a single product since such combination would allow for the use to detect the combination of autoantibodies, thereby increasing the predictive/diagnostic value of the product. A person having ordinary skill in the art would have had a reasonable expectation of success given that the 'multimarker' strategy presents a benefit with regards to risk stratification and Kronimus et al. teach MAPT autoantibody levels can identify demented vs. non-demented Parkinson’s disease patients.
It would have been further prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Nagele in view of Rouslahti, Papuc, Valkirs et al. Coleman, and Kronimus et al. , namely to rely on the SEQ. ID NO. 1 fragment taught by Moe and Davidwitz as the MAPT protein fragment, because Moe and Davidwitz teach a small, finite number of identified fragments “where tau cuts itself” (paragraph 123), thereby making it obvious for the common artisan to try one of the list of possible candidates of protein fragments related to neurodegenerative disease. There would be a reasonable expectation of success because Moe and Davidwitz disclose the molecular weight, isoelectric point and estimated charge at pH 7.4 of the protein fragment.
Claims 6, 8, 15 an d 19 are rejected under 35 U.S.C. 103 as being unpatentable over Nagele in view of Rouslahti as applied to claim 4 above, and further in view of Schmidt et al. (WO 2012/170993)-Cite No. R of PTO892 3/19/2025 ("Schmidt").
Regarding claims 6, 8, 15 and 19, Nagele in view of Rouslahti teach the combination of claims 1 and 4 as discussed above.
Nagele further teaches that Parkinson’s disease is a central nervous system disorder causing neurological damage (“The cardinal pathological feature of PD is the loss of dopaminergic neurons in the substantia nigra, a brain region involved in coordination and control of muscle activity” paragraph 2). Nagele further suggests that Parkinson’s disease is associated with myeloid malignancies (“PD diagnostic biomarkers are set forth in the following Table 1” paragraph 12, “myeloid/lymphoid or mixed-lineage leukemia” page 8).
Nagele in view of Rouslahti fail to teach the RAGE protein fragment shown in SEQ ID NO:7.
Schmidt teaches that “Amyloid deposition plays an important role in the pathology of many human diseases” (page 2 line 18). Schmidt further teaches that “[s]ome inhibitors of amyloid formation…prolong the lag phase, extend the time course of toxicity” (page 2 lines 30-31). Schmidt further teaches “[i]n an embodiment thereof, the amyloidosis is diabetes, Alzheimer's Disease (AD), or Parkinson's Disease (PD). In a particular embodiment thereof, the inhibitor of amyloidogenic polypeptide self-aggregation into amyloids or the prophylactic and/or therapeutic agent is sRAGE [soluble RAGE]” (page 7 lines 5-8). Schmidt further teaches “the amino acid sequence of soluble RAGE (SEQ ID NO: 18)” (page 16 lines 28-34). Note that SEQ ID NO:18 of Schmidt has a 100% match to SEQ ID NO:7 of the instant claim. Schmidt further teaches that “IAPP [islet amyloid polypeptide] toxic oligomers may also serve as diagnostic markers” (page 22 lines 17-18).
It would have been further prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Nagele in view of Rouslahti to include the RAGE protein fragment shown in SEQ ID NO:7 taught by Schmidt because Schmidt teaches that the RAGE protein in SEQ ID NO:7 is used to treat Parkinson's disease and Nagele, in view of Rouslahti teach methods and/or compositions for diagnosing Parkinson’s disease. One would have been motivated to make such a modification because work in one field of endeavor may prompt variations. In this case, the scope and content of the prior art included a similar product, i.e., a protein biomarkers of Parkinson’s disease. Given that Parkinson’s disease is an art-recognized problem, there is an incentive to adapt the base product, i.e., a protein, to include variations, namely to treat Parkinson’s disease. A person having ordinary skill in the art would have had a reasonable expectation of success because Schmidt and Nagele in view of Rouslahti teach methods and/or compositions related to Parkinson’s disease and the scope of Schmidt also encompassed the use of proteins as diagnostic biomarkers.
Claims 7 and 16-17 are rejected under 35 U.S.C. 103 as being unpatentable over Nagele in view of Rouslahti as applied to claims 3-4 above, and further in view of Daffo et al. (WO 02/097031 A2)-Cite No. N of PTO892 3/19/2025 ("Daffo") and Riessland et al. Cell Stem Cell Volume 25, Issue 4, 3 October 2019, Pages 514-530.e8-Cite No. U of PTO892 3/19/2025 (“Riessland”).
Regarding claims 7 and 16, Nagele in view of Rouslahti teach the protein combination according to claims 3-4 as discussed above.
Nagele in view of Rouslahti fail to teach SEQ ID NO:4.
Daffo teaches “An isolated polypeptide selected from the group consisting of: a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:671-1347” (claim 27 page 589). Note that SEQ ID NO:792 of Daffo is 100% matched to SEQ ID NO:4 of the instant claim. Daffo further teaches “Sequences of Human Diagnostic and Therapeutic Molecules. The dithp of the present invention may be used for a variety of diagnostic and therapeutic purposes. For example… Parkinson's disease” (page 137 lines 17-19 and page 140 lines 4-5). Note that although Daffo fails to use the language P21, the teachings of the SEQ ID NO:4 implicitly teaches the P21 protein because the P21 protein comprises the sequence shown in SEQ ID NO:4. Daffo teaches the P21 protein from a long list of proteins used to diagnose and treat Parkinson’s disease from a long list of diseases.
Riessland teaches that “[a] key pathological hallmark of Parkinson’s disease (PD) is the progressive degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) of the midbrain. Loss of these cells causes the characteristic motor symptoms of the disease” (page 514 column 1 paragraph 2). Riessland further teaches “that p21 is actively expressed in the dopamine neurons of the SNpc of sporadic PD patients” (page 516 column 1 paragraph 3). Therefore, given that p21 is actively expressed in the dopamine neurons of the SNpc in Parkinson’s disease patients, and that loss of the dopamine neurons of the SNpc causes the characteristic motor symptoms of Parkinson’s disease, Riessland teaches that p21 is associated with Parkinson’s disease.
It would have been further prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Nagele in view of Rouslahti to rely on the P21 protein fragment shown in SEQ ID NO:4 taught by Daffo because Daffo teaches that the P21 protein fragment shown in SEQ ID NO:4 is used to diagnose and treat Parkinson's disease and Riessland teaches that the P21 protein is associated with Parkinson’s disease. Therefore, applying the P21 protein fragment shown in SEQ ID NO:4 taught by Daffo to the art-recognized technique of using P21 for diagnosing Parkinson’s disease taught by both Daffo and Nagele would have been obvious to a person having ordinary skill in the art. One would have been motivated to make such a modification because Daffo teaches that the P21 protein fragment shown in SEQ ID NO:4 is also used to treat Parkinson’s disease. A person having ordinary skill in the art would have had a reasonable expectation of success because Daffo, Riessland, Nagele and Rouslahti teach methods and/or compositions related to Parkinson’s disease.
Regarding claim 17, Nagele in view of Rouslahti, Daffo and Riessland teach the protein antigen combination according to claim 16 as discussed above.
Nagele in view of Rouslahti, Daffo and Riessland further teach wherein the DAG fragment has the sequence shown in SEQ ID NO:5 (para. 25 of Rouslahti).
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Nagele in view of Rouslahti as applied to claim 4 above, and further in view of Papuc, Valkirs, Coleman, Schmidt, Daffo and Riessland.
Regarding claim 20, Nagele in view of Rouslahti teach the protein combination according to claim 4 as discussed above.
Nagele in view of Rouslahti fail to teach comprising the HSP60 protein having the sequence shown in SEQ ID NO:3, the RAGE protein fragment shown in SEQ ID NO:7, and SEQ ID NO:4.
Papuc teaches “Humoral Response against Small Heat Shock Proteins in Parkinson’s Disease” (Title). Papuc teaches using HSP60 protein to detect “anti-HSP 60 autoantibodies…in serum of parkinsonian patients and healthy controls” (page 7 para. 4). Note that although Papuc did not detect a statistical significant difference in anti-HSP60 autoantibodies between PD patients and controls, Papuc still suggests that the Parkinson’s disease has an “inducing effect” in the humoral response (page 7 para. 4). Papuc further suggests using HSP60 “to delineate immune response typical for PD. This in turn could be potentially helpful to find the surrogate markers for this chronic neurodegenerative disorder” (page 7 para. 5).
Valkirs et al. teach methods for the diagnosis and evaluation, specifically early detection and differentiation, of a health condition based on sample analysis regarding the presence and amount of members of a panel of markers (Abstract). Valkirs et al. further teach combining a plurality of makers can “increase the predictive value of the analysis” in comparison to an analysis of individual markers (paragraph 17); and particularly the 'multimarker' strategy presents a benefit with regards to risk stratification (paragraph 184).
Coleman teaches “biomarkers of neurodegenerative disease” (Title). Coleman further teaches that “[s]pecific examples of these biomarkers include, but are not limited to, HSP60” (paragraph 127). Coleman further teaches that “[t]he disclosed compositions can be used in a variety of ways as research tools. For example, the disclosed compositions, such as SEQ ID NOs: 1-257 can be used to study the effects of various therapies on a neurodegenerative disease The compositions can be used for example as targets in combinatorial chemistry protocols or other screening protocols to isolate molecules that possess desired functional properties related to a neurodegenerative disease (e.g., Alzheimer's and Parkinson's disease). The disclosed compositions can also be used diagnostic tools related to neurodegenerative diseases such as Alzheimer's and Parkinson's disease” (paragraphs 253-255). Note that SEQ ID NO:241 is 100% matched to SEQ ID NO:3 of the instant invention.
Schmidt teaches that “Amyloid deposition plays an important role in the pathology of many human diseases” (page 2 line 18). Schmidt further teaches that “[s]ome inhibitors of amyloid formation…prolong the lag phase, extend the time course of toxicity” (page 2 lines 30-31). Schmidt further teaches “[i]n an embodiment thereof, the amyloidosis is diabetes, Alzheimer's Disease (AD), or Parkinson's Disease (PD). In a particular embodiment thereof, the inhibitor of amyloidogenic polypeptide self-aggregation into amyloids or the prophylactic and/or therapeutic agent is sRAGE [soluble RAGE]” (page 7 lines 5-8). Schmidt further teaches “the amino acid sequence of soluble RAGE (SEQ ID NO: 18)” (page 16 lines 28-34). Note that SEQ ID NO:18 of Schmidt has a 100% match to SEQ ID NO:7 of the instant claim. Schmidt further teaches that “IAPP [islet amyloid polypeptide] toxic oligomers may also serve as diagnostic markers” (page 22 lines 17-18).
Daffo teaches “An isolated polypeptide selected from the group consisting of: a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:671-1347” (claim 27 page 589). Note that SEQ ID NO:792 of Daffo is 100% matched to SEQ ID NO:4 of the instant claim. Daffo further teaches “Sequences of Human Diagnostic and Therapeutic Molecules. The dithp of the present invention may be used for a variety of diagnostic and therapeutic purposes. For example… Parkinson's disease” (page 137 lines 17-19 and page 140 lines 4-5). Note that although Daffo fails to use the language P21, the teachings of the SEQ ID NO:4 implicitly teaches the P21 protein because the P21 protein comprises the sequence shown in SEQ ID NO:4. Daffo teaches the P21 protein from a long list of proteins used to diagnose and treat Parkinson’s disease from a long list of diseases.
Riessland teaches that “[a] key pathological hallmark of Parkinson’s disease (PD) is the progressive degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) of the midbrain. Loss of these cells causes the characteristic motor symptoms of the disease” (page 514 column 1 paragraph 2). Riessland further teaches “that p21 is actively expressed in the dopamine neurons of the SNpc of sporadic PD patients” (page 516 column 1 paragraph 3). Therefore, given that p21 is actively expressed in the dopamine neurons of the SNpc in Parkinson’s disease patients, and that loss of the dopamine neurons of the SNpc causes the characteristic motor symptoms of Parkinson’s disease, Riessland teaches that p21 is associated with Parkinson’s disease.
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 modify the teachings of Nagele in view of Rouslahti namely including HSP60, taught by Papuc, in the protein antigen combination, thereby arriving at the present claim, (i.e., to provide the combination of proteins together), because Valkirs et al. teach that combining makers can increase the predictive value of the analysis and both Nagele and Papuc teach protein antigen biomarkers of Parkinson’s disease. One would have been motivated to make such a modification in order to receive the expected benefit of diagnosing Parkinson's disease earlier, thereby slowing the progression of the disease, minimizing symptoms, and improving the overall quality of life as taught by Nagele, specifically combining the proteins together as a single product since such combination would allow for the use to detect the combination of autoantibodies, thereby increasing the predictive/diagnostic value of the product. A person having ordinary skill in the art would have had a reasonable expectation of success given that both Nagele and Papuc teach protein antigens for detecting Parkinson’s Disease.
It would have been further prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Nagele in view of Rouslahti, Papuc and Valkirs et al. to rely on HSP60 shown in SEQ ID NO:3 taught by Coleman because Coleman teaches that HSP60 shown in SEQ ID NO:3 is used to diagnose Parkinson's disease. Therefore, applying the HSP60 protein fragment shown in SEQ ID NO:3 taught by Coleman to the art-recognized technique of using HSP60 as a biomarker of Parkinson’s disease taught by both Papuc and Coleman would have been obvious to a person having ordinary skill in the art. One would have been motivated to make such a modification because Nagele teaches that diagnosing PD early can increase the quality of life of the patient. A person having ordinary skill in the art would have had a reasonable expectation of success because Coleman teaches SEQ ID NO:3 in the context of neurodegenerative diseases, i.e., Parkinson’s disease, and Nagele in view of Rouslahti, Papuc and Valkirs et al. teach protein antigen combinations for detecting Parkinson’s Disease.
It would have been further prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Nagele in view of Rouslahti, Papuc, Valkirs and Coleman to include the RAGE protein fragment shown in SEQ ID NO:7 taught by Schmidt because Schmidt teaches that the RAGE protein in SEQ ID NO:7 is used to treat Parkinson's disease and Nagele, in view of Rouslahti, Papuc, Valkirs and Coleman teach methods and/or compositions for diagnosing Parkinson’s disease. One would have been motivated to make such a modification because work in one field of endeavor may prompt variations. In this case, the scope and content of the prior art included a similar product, i.e., a protein biomarkers of Parkinson’s disease. Given that Parkinson’s disease is an art-recognized problem, there is an incentive to adapt the base product, i.e., a protein, to include variations, namely to treat Parkinson’s disease. A person having ordinary skill in the art would have had a reasonable expectation of success because Schmidt and Nagele in view of Rouslahti, Papuc, Valkirs and Coleman teach methods and/or compositions related to Parkinson’s disease and the scope of Schmidt also encompassed the use of proteins as diagnostic biomarkers.
It would have been further prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Nagele in view of Rouslahti, Papuc, Valkirs, Coleman and Schmidt to rely on the P21 protein fragment shown in SEQ ID NO:4 taught by Daffo because Daffo teaches that the P21 protein fragment shown in SEQ ID NO:4 is used to diagnose and treat Parkinson's disease and Riessland teaches that the P21 protein is associated with Parkinson’s disease. Therefore, applying the P21 protein fragment shown in SEQ ID NO:4 taught by Daffo to the art-recognized technique of using P21 for diagnosing Parkinson’s disease taught by both Daffo and Nagele would have been obvious to a person having ordinary skill in the art. One would have been motivated to make such a modification because Daffo teaches that the P21 protein fragment shown in SEQ ID NO:4 is also used to treat Parkinson’s disease. A person having ordinary skill in the art would have had a reasonable expectation of success because Daffo, Riessland and Nagele in view of Rouslahti, Papuc, Valkirs, Coleman and Schmidt teach methods and/or compositions related to Parkinson’s disease.
Double Patenting
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.
Copending Application No. 19206017
Claims 1, 10-11 and 21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 19206017 in view of Nagele.
Regarding claims 1 and 21, copending Application No. 19206017 recites a protein antigen combination, comprising at least two protein fragments selected from the group consisting of an ADARB1 fragment show in SEQ ID NO:2, a protein p21 fragment shown in SEQ ID NO:4, a DNAJC8 fragment shown in SEQ ID NO:6, an ASXL1 fragment shown in SEQ ID NO:8, and a JMJD2D fragment shown in SEQ ID NO:9 (“The antigen combination according to claim 10, wherein the P21 protein fragment has the amino acid sequence shown in SEQ ID NO:2, the DNAJC8 protein fragment has the amino acid sequence shown in SEQ ID NO:3, the JMJD2D protein fragment has the amino acid sequence shown in SEQ ID NO:6, the MAPT protein fragment has the amino acid sequence shown in SEQ ID NO:1, the RAGE protein fragment has the amino acid sequence shown in SEQ ID NO:4, and the ASXLI protein fragment has the amino acid sequence shown in SEQ ID NO:5” claim 11). Note that the sequences recited by copending Application No. 19206017 are 100% matched to the sequences claimed in the instant case. Furthermore, the recitation of “the combination being configured to detect Alzheimer's disease with an overall sensitivity greater than 85 % and an overall specificity greater than 88 %,” fails to impart any structural limitation to the protein antigen combination claimed; the combination itself, i.e. the specific sequences of the fragments are reasonably considered to be inherently configured to detect Alzheimer's disease with an overall sensitivity greater than 85 % and an overall specificity greater than 88 % as these protein fragments are indistinguishable from the protein fragments of the instant invention.
Copending Application No. 19206017 fails to recite wherein each protein fragment of the protein antigen combination is fused to a heterologous tag, wherein the heterologous comprises a HIS tag or a c-myc tag.
Nagele teaches a protein antigen combination, comprising at least two protein fragments selected from the group consisting of an ADARB1 fragment show in SEQ ID NO:2, a protein p21, a DNAJC8 fragment shown in SEQ ID NO:6, an ASXL1 fragment shown in SEQ ID NO:8, and a JMJD2D fragment shown in SEQ ID NO:9 (Abstract, Table 1 pages 7-9 and 12). Nagele further suggests wherein each protein fragment of the protein antigen combination is fused to a heterologous tag, wherein the heterologous comprises a HIS tag or a c-myc tag (para. 22, para. 24). Nagele further teaches that Parkinson’s disease is a common and serious disease “inflicting profound social and economic costs worldwide” (para. 2). Nagele further teaches that there is “widespread recognition that early detection facilitating early treatment helps to slow the progression of the disease, minimize symptoms, and improve the overall quality of life” (para. 4) and teaches the use of the protein antigens of Table 1 to identify autoantibodies of PD (para. 12).
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 copending Application No. 19206017 to rely on the HIS tag taught by Nagele because Nagele suggests this enables the purification of the protein. A person having ordinary skill in the art would have had a reasonable expectation of success because both of copending Application No. 19206017 and Nagele teach an ADARB1 fragment show in SEQ ID NO:2, a protein p21, a DNAJC8 fragment shown in SEQ ID NO:6, an ASXL1 fragment shown in SEQ ID NO:8, and a JMJD2D fragment shown in SEQ ID NO:9.
Regarding claim 10, copending Application No. 19206017 recites a kit for detecting Alzheimer's disease, comprising the protein antigen combination according to claim 1 (“A kit for distinguishing Alzheimer's disease from frontotemporal dementia and dementia with Lewy bodies, comprising the antigen combination according to claim 2” claim 18, “The kit according to claim 19, further comprising a MAPT protein fragment having the amino acid sequence shown in SEQ ID NO: l, a RAGE protein fragment having the amino acid sequence shown in SEQ ID NO:4, an ASXL1 protein fragment having the amino acid sequence shown in SEQ ID NO:5, a JMJD2D protein fragment having the amino acid sequence shown in SEQ ID NO:6, a P21 protein fragment having the amino acid sequence shown in SEQ ID NO:2, and a DNAJC8 protein fragment having the amino acid sequence shown in SEQ ID NO:3” claim 20).
Copending Application No. 19206017 fails to recite purified and prepared for detecting autoantibodies against at least one of the protein fragment in a biological sample; a labeled anti-human antibody that binds to the autoantibodies; and a chromogenic agent that changes an absorbance of light at a predetermined wavelength in a test sample containing the protein antigen combination, the autoantibodies and the labeled anti-human antibody.
Nagele teaches the protein antigen combination of claim 1 (see above), “purified” (paragraph 26) and prepared for “detecting… autoantibodies” (paragraph 12) against at least one of the protein fragments in a biological sample (paragraphs 21-22); and a labeled anti-human antibody that binds to the autoantibodies; and a chromogenic agent that changes an absorbance of light at a predetermined wavelength (“anti-human IgG (H+L) conjugated to AlexaFluor 647” paragraphs 48-49) in a test sample containing the protein antigen combination, the autoantibodies and the labeled anti-human antibody (paragraph 21).
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 copending Application No. 19206017 to include on the kit the combination, purified and prepared for detecting autoantibodies, a labeled anti-human antibody that binds to the autoantibodies; and a chromogenic agent taught by Nagele because Nagele suggests this enables the diagnosis of Parkinson’s disease, which is a current need in the field as early detection of PD increases the quality of life of the patient. A person having ordinary skill in the art would have had a reasonable expectation of success because both copending Application No. 19206017 and Nagele teach the protein antigen combination of claim 1.
Regarding claim 11, similarly as discussed above, the particular sample which the kit is intended to be used on is specific to the intended use of the claimed kit (the sample is not a structural component of the kit itself). Nonetheless, it is noted that Nagele teaches wherein the biological sample is whole blood or serum (paragraph 20). As a result, it would be expected that the kit (combination of proteins as taught by Nagele) would similarly be capable of the intended use applied to samples as claimed.
Claims 3-4 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 19206017 in view of Nagele as applied to claim 1 above, and further in view of Rouslahti et al. (US 11571485 B2) ("Rouslahti").
Regarding claims 3-4, copending Application No. 19206017 in view of Nagele teach the protein antigen combination according to claim 1 as discussed above.
Copending Application No. 19206017 in view of Nagele fail to recite a DAG fragment shown in SEQ ID NO:5.
Rouslahti teaches “peptides and antibodies for detecting changes in Alzheimer’s disease brain and methods of use thereof” (Title). Rouslahti further teaches that “the peptide has an amino acid sequence as set forth in SEQ ID NO: 102 (CDAGRKQKC; also herein referred to as “DAG”)” (para. 25). Note that SEQ ID NO: 102 (CDAGRKQKC) is 100% matched to SEQ ID NO:5 claimed. Rouslahti also teaches that the peptide “DAG (SEQ ID NO: 102)… homed to cells in human…Parkinson's disease brain” (para. 165) and suggests the use of DAG as an imaging biomarker for Parkinson’s disease (para. 221).
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 copending Application No. 19206017 in view of Nagele to include the DAG fragment shown in SEQ ID NO:5 taught by Rouslahti because Nagele teaches that PD is a current health crisis and Rouslahti teaches that the DAG fragment shown in SEQ ID NO:5 can be used as an imaging biomarker for PD. A person having ordinary skill in the art would have had a reasonable expectation of success because both copending Application No. 19206017 in view of Nagele and Rouslahti are drawn to peptides related to disease detection.
Claims 5, 13-14 and 18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 19206017 in view of Nagele and Rouslahti as applied to claims 3-4 above, and further in view of Papuc, Valkirs, Coleman, Kronimus and Moe and Davidwits.
Regarding claims 5, 13-14 and 18, copending Application No. 19206017 in view of Nagele and Rouslahti teach the combination of claims 3-4 as discussed above.
Copending Application No. 19206017 in view of Nagele and Rouslahti fail to recite comprising the MAPT protein fragment shown in SEQ ID NO:1, and the HSP60 protein fragment shown in SEQ ID NO:3.
Papuc, Valkirs, Coleman, Kronimus and Moe and Davidwits are relied upon as in the 103 rejection above.
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 modify the teachings of copending Application No. 19206017 in view of Nagele and Rouslahti namely including HSP60, taught by Papuc, in the protein antigen combination, thereby arriving at the present claim, (i.e., to provide the combination of proteins together), because Valkirs et al. teach that combining makers can increase the predictive value of the analysis and both copending Application No. 19206017 in view of Nagele and Papuc teach protein antigen biomarkers of Parkinson’s disease. One would have been motivated to make such a modification in order to receive the expected benefit of diagnosing Parkinson's disease earlier, thereby slowing the progression of the disease, minimizing symptoms, and improving the overall quality of life as taught by Nagele, specifically combining the proteins together as a single product since such combination would allow for the use to detect the combination of autoantibodies, thereby increasing the predictive/diagnostic value of the product. A person having ordinary skill in the art would have had a reasonable expectation of success given that both copending Application No. 19206017 in view of Nagele and Papuc teach protein antigens for detecting Parkinson’s Disease.
It would have been further prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of copending Application No. 19206017 in view of Nagele, Rouslahti, Papuc and Valkirs et al. to rely on HSP60 shown in SEQ ID NO:3 taught by Coleman because Coleman teaches that HSP60 shown in SEQ ID NO:3 is used to diagnose Parkinson's disease. Therefore, applying the HSP60 protein fragment shown in SEQ ID NO:3 taught by Coleman to the art-recognized technique of using HSP60 as a biomarker of Parkinson’s disease taught by both Papuc and Coleman would have been obvious to a person having ordinary skill in the art. One would have been motivated to make such a modification because copending Application No. 19206017 in view of Nagele teach that diagnosing PD early can increase the quality of life of the patient. A person having ordinary skill in the art would have had a reasonable expectation of success because Coleman teaches SEQ ID NO:3 in the context of neurodegenerative diseases, i.e., Parkinson’s disease, and copending Application No. 19206017 in view of Nagele, Rouslahti, Papuc and Valkirs et al. teach protein antigen combinations for detecting Parkinson’s Disease.
It would have been further prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of copending Application No. 19206017 in view of Nagele in view of Rouslahti, Papuc, Valkirs et al. and Coleman to include the MAPT protein taught by Kronimus et al. (i.e., to provide the combination of proteins together), thereby arriving at the instant claim, because Valkirs et al. teach that combining makers can increase the predictive value of the analysis and both copending Application No. 19206017 in view of Nagele and Kronimus et al. teach protein antigens to detect the related autoantibody makers shown to be associated with Parkinson’s disease. One would have been motivated to make such a modification in order to receive the expected benefit of diagnosing Parkinson's disease earlier, thereby slowing the progression of the disease, minimizing symptoms, and improving the overall quality of life as taught by Nagele, specifically combining the proteins together as a single product since such combination would allow for the use to detect the combination of autoantibodies, thereby increasing the predictive/diagnostic value of the product. A person having ordinary skill in the art would have had a reasonable expectation of success given that the 'multimarker' strategy presents a benefit with regards to risk stratification and Kronimus et al. teach MAPT autoantibody levels can identify demented vs. non-demented Parkinson’s disease patients.
It would have been further prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of copending Application No. 19206017 in view of Nagele, Rouslahti, Papuc, Valkirs et al. Coleman, and Kronimus et al. , namely to rely on the SEQ. ID NO. 1 fragment taught by Moe and Davidwitz as the MAPT protein fragment, because Moe and Davidwitz teach a small, finite number of identified fragments “where tau cuts itself” (paragraph 123), thereby making it obvious for the common artisan to try one of the list of possible candidates of protein fragments related to neurodegenerative disease. There would be a reasonable expectation of success because Moe and Davidwitz disclose the molecular weight, isoelectric point and estimated charge at pH 7.4 of the protein fragment.
Claims 6, 8, 15 and 19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 19206017 in view of Nagele and Rouslahti as applied to claim 4 above, and further in view of Schmidt.
Regarding claims 6, 8, 15 and 19, copending Application No. 19206017 in view of Nagele and Rouslahti teach the combination of claims 1 and 4 as discussed above.
Nagele further teaches that Parkinson’s disease is a central nervous system disorder causing neurological damage (paragraph 2). Nagele further suggests that Parkinson’s disease is associated with myeloid malignancies (page 8).
Copending Application No. 19206017 in view of Nagele and Rouslahti fail to recite the RAGE protein fragment shown in SEQ ID NO:7.
Schmidt is relied upon as in the 103 rejection above.
It would have been further prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of copending Application No. 19206017 in view of Nagele and Rouslahti to include the RAGE protein fragment shown in SEQ ID NO:7 taught by Schmidt because Schmidt teaches that the RAGE protein in SEQ ID NO:7 is used to treat Parkinson's disease and copending Application No. 19206017 in view of Nagele, and Rouslahti teach methods and/or compositions for diagnosing Parkinson’s disease. One would have been motivated to make such a modification because work in one field of endeavor may prompt variations. In this case, the scope and content of the prior art included a similar product, i.e., a protein biomarkers of Parkinson’s disease. Given that Parkinson’s disease is an art-recognized problem, there is an incentive to adapt the base product, i.e., a protein, to include variations, namely to treat Parkinson’s disease. A person having ordinary skill in the art would have had a reasonable expectation of success because Schmidt and copending Application No. 19206017 in view of Nagele and Rouslahti teach methods and/or compositions related to Parkinson’s disease and the scope of Schmidt also encompassed the use of proteins as diagnostic biomarkers.
Claims 7 and 16-17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 19206017 in view of Nagele and Rouslahti as applied to claims 3-4 above, and further in view of Daffo and Riessland.
Regarding claims 7 and 16, copending Application No. 19206017 in view of Nagele and Rouslahti teach the protein combination according to claims 3-4 as discussed above.
Copending Application No. 19206017 in view of Nagele and Rouslahti fail to recite SEQ ID NO:4.
Daffo and Riessland are relied upon as in the 103 rejection above.
It would have been further prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of copending Application No. 19206017 in view of Nagele and Rouslahti to rely on the P21 protein fragment shown in SEQ ID NO:4 taught by Daffo because Daffo teaches that the P21 protein fragment shown in SEQ ID NO:4 is used to diagnose and treat Parkinson's disease and Riessland teaches that the P21 protein is associated with Parkinson’s disease. Therefore, applying the P21 protein fragment shown in SEQ ID NO:4 taught by Daffo to the art-recognized technique of using P21 for diagnosing Parkinson’s disease taught by both Daffo and copending Application No. 19206017 in view of Nagele would have been obvious to a person having ordinary skill in the art. One would have been motivated to make such a modification because Daffo teaches that the P21 protein fragment shown in SEQ ID NO:4 is also used to treat Parkinson’s disease. A person having ordinary skill in the art would have had a reasonable expectation of success because Daffo, Riessland and copending Application No. 19206017 in view of Nagele and Rouslahti teach methods and/or compositions related to Parkinson’s disease.
Regarding claim 17, copending Application No. 19206017 in view of Nagele, Rouslahti, Daffo and Riessland teach the protein antigen combination according to claim 16 as discussed above.
Copending Application No. 19206017 in view of Nagel, Rouslahti, Daffo and Riessland further teach wherein the DAG fragment has the sequence shown in SEQ ID NO:5 (para. 25 of Rouslahti).
Claim 20 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 19206017 in view of Nagele and Rouslahti as applied to claim 4 above, and further in view of Papuc, Valkirs, Coleman, Schmidt, Daffo and Riessland.
Regarding claim 20, copending Application No. 19206017 in view of Nagele and Rouslahti teach the protein combination according to claim 4 as discussed above.
Copending Application No. 19206017 in view of Nagele and Rouslahti fail to recite comprising the HSP60 protein having the sequence shown in SEQ ID NO:3, the RAGE protein fragment shown in SEQ ID NO:7, and SEQ ID NO:4.
Papuc, Valkirs, Coleman, Schmidt, Daffo and Riessland are relied upon as in the 103 rejection above.
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 modify the teachings of copending Application No. 19206017 in view of Nagele and Rouslahti namely including HSP60, taught by Papuc, in the protein antigen combination, thereby arriving at the present claim, (i.e., to provide the combination of proteins together), because Valkirs et al. teach that combining makers can increase the predictive value of the analysis and both copending Application No. 19206017 in view of Nagele and Papuc teach protein antigen biomarkers of Parkinson’s disease. One would have been motivated to make such a modification in order to receive the expected benefit of diagnosing Parkinson's disease earlier, thereby slowing the progression of the disease, minimizing symptoms, and improving the overall quality of life as taught by Nagele, specifically combining the proteins together as a single product since such combination would allow for the use to detect the combination of autoantibodies, thereby increasing the predictive/diagnostic value of the product. A person having ordinary skill in the art would have had a reasonable expectation of success given that both copending Application No. 19206017 in view of Nagele and Papuc teach protein antigens for detecting Parkinson’s Disease.
It would have been further prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of copending Application No. 19206017 in view of Nagele, Rouslahti, Papuc and Valkirs et al. to rely on HSP60 shown in SEQ ID NO:3 taught by Coleman because Coleman teaches that HSP60 shown in SEQ ID NO:3 is used to diagnose Parkinson's disease. Therefore, applying the HSP60 protein fragment shown in SEQ ID NO:3 taught by Coleman to the art-recognized technique of using HSP60 as a biomarker of Parkinson’s disease taught by both Papuc and Coleman would have been obvious to a person having ordinary skill in the art. One would have been motivated to make such a modification because copending Application No. 19206017 in view of Nagele teach that diagnosing PD early can increase the quality of life of the patient. A person having ordinary skill in the art would have had a reasonable expectation of success because Coleman teaches SEQ ID NO:3 in the context of neurodegenerative diseases, i.e., Parkinson’s disease, and copending Application No. 19206017 in view of Nagele, Rouslahti, Papuc and Valkirs et al. teach protein antigen combinations for detecting Parkinson’s Disease.
It would have been further prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of copending Application No. 19206017 in view of Nagele, Rouslahti, Papuc, Valkirs and Coleman to include the RAGE protein fragment shown in SEQ ID NO:7 taught by Schmidt because Schmidt teaches that the RAGE protein in SEQ ID NO:7 is used to treat Parkinson's disease and copending Application No. 19206017 in view of Nagele, Rouslahti, Papuc, Valkirs and Coleman teach methods and/or compositions for diagnosing Parkinson’s disease. One would have been motivated to make such a modification because work in one field of endeavor may prompt variations. In this case, the scope and content of the prior art included a similar product, i.e., a protein biomarkers of Parkinson’s disease. Given that Parkinson’s disease is an art-recognized problem, there is an incentive to adapt the base product, i.e., a protein, to include variations, namely to treat Parkinson’s disease. A person having ordinary skill in the art would have had a reasonable expectation of success because Schmidt and copending Application No. 19206017 in view of Nagele, Rouslahti, Papuc, Valkirs and Coleman teach methods and/or compositions related to Parkinson’s disease and the scope of Schmidt also encompassed the use of proteins as diagnostic biomarkers.
It would have been further prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of copending Application No. 19206017 in view of Nagele, Rouslahti, Papuc, Valkirs, Coleman and Schmidt to rely on the P21 protein fragment shown in SEQ ID NO:4 taught by Daffo because Daffo teaches that the P21 protein fragment shown in SEQ ID NO:4 is used to diagnose and treat Parkinson's disease and Riessland teaches that the P21 protein is associated with Parkinson’s disease. Therefore, applying the P21 protein fragment shown in SEQ ID NO:4 taught by Daffo to the art-recognized technique of using P21 for diagnosing Parkinson’s disease taught by both Daffo and copending Application No. 19206017 in view of Nagele would have been obvious to a person having ordinary skill in the art. One would have been motivated to make such a modification because Daffo teaches that the P21 protein fragment shown in SEQ ID NO:4 is also used to treat Parkinson’s disease. A person having ordinary skill in the art would have had a reasonable expectation of success because Daffo, Riessland and copending Application No. 19206017 in view of Nagele, Rouslahti, Papuc, Valkirs, Coleman and Schmidt teach methods and/or compositions related to Parkinson’s disease.
Copending Application No. 18996523
Claims 1, 10-11 and 21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 11-13 and 15 of copending Application No. 18996523 in view of Nagele.
Regarding claims 1 and 21, copending Application No. 18996523 recites a protein antigen combination, comprising at least two protein fragments selected from the group consisting of an ADARB1 fragment show in SEQ ID NO:2, a DNAJC8 fragment shown in SEQ ID NO:6, and a JMJD2D fragment shown in SEQ ID NO:9 (“An antigen combination for diagnosis of early Alzheimer's disease, wherein the antigen combination comprises…KDM4D [JMJD2D] comprises the amino acid sequence set forth in SEQ ID NO: 7, ADARB 1 comprises the amino acid sequence set forth in SEQ ID NO: 9” claim 11, “DNAJC8 comprises the amino acid sequence set forth in SEQ ID NO: 8” claim 13). Note that the sequences recited by copending Application No. 18996523 are 100% matched to the sequences claimed in the instant case. Furthermore, the recitation of “the combination being configured to detect Alzheimer's disease with an overall sensitivity greater than 85 % and an overall specificity greater than 88 %,” fails to impart any structural limitation to the protein antigen combination claimed; the combination itself, i.e. the specific sequences of the fragments are reasonably considered to be inherently configured to detect Alzheimer's disease with an overall sensitivity greater than 85 % and an overall specificity greater than 88 % as these protein fragments are indistinguishable from the protein fragments of the instant invention. Copending Application No. 18996523further recites “wherein at least one of…KDM4D, and ADARB 1 is labeled with a tag for purification or identification” (claim 11).
Copending Application No. 18996523 fails to recite wherein each protein fragment of the protein antigen combination is fused to a heterologous tag, wherein the heterologous comprises a HIS tag or a c-myc tag.
Nagele teaches a protein antigen combination, comprising at least two protein fragments selected from the group consisting of an ADARB1 fragment show in SEQ ID NO:2, a protein p21, a DNAJC8 fragment shown in SEQ ID NO:6, an ASXL1 fragment shown in SEQ ID NO:8, and a JMJD2D fragment shown in SEQ ID NO:9 (Abstract, Table 1 pages 7-9 and 12). Nagele further suggests wherein each protein fragment of the protein antigen combination is fused to a heterologous tag, wherein the heterologous comprises a HIS tag or a c-myc tag (para. 22, para. 24). Nagele further teaches that Parkinson’s disease is a common and serious disease “inflicting profound social and economic costs worldwide” (para. 2). Nagele further teaches that there is “widespread recognition that early detection facilitating early treatment helps to slow the progression of the disease, minimize symptoms, and improve the overall quality of life” (para. 4) and teaches the use of the protein antigens of Table 1 to identify autoantibodies of PD (para. 12).
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 copending Application No. 18996523 to rely on the HIS tag taught by Nagele because Nagele suggests this enables the diagnosis of Parkinson's disease, which is a current health crisis. A person having ordinary skill in the art would have had a reasonable expectation of success because both of copending Application No. 18996523 and Nagele teach an ADARB1 fragment show in SEQ ID NO:2, a DNAJC8 fragment shown in SEQ ID NO:6, and a JMJD2D fragment shown in SEQ ID NO:9.
Regarding claim 10, copending Application No. 18996523 recites a kit for detecting Alzheimer's disease, comprising the protein antigen combination according to claim 1 (“[a] reagent or kit for diagnosing/detecting early Alzheimer's disease, comprising the antigen combination according to claim 11” claim 15).
Copending Application No. 18996523 fails to recite purified and prepared for detecting autoantibodies against at least one of the protein fragment in a biological sample; a labeled anti-human antibody that binds to the autoantibodies; and a chromogenic agent that changes an absorbance of light at a predetermined wavelength in a test sample containing the protein antigen combination, the autoantibodies and the labeled anti-human antibody.
Nagele teaches the protein antigen combination of claim 1 (see above), “purified” (paragraph 26) and prepared for “detecting… autoantibodies” (paragraph 12) against at least one of the protein fragments in a biological sample (paragraphs 21-22); and a labeled anti-human antibody that binds to the autoantibodies; and a chromogenic agent that changes an absorbance of light at a predetermined wavelength (“anti-human IgG (H+L) conjugated to AlexaFluor 647” paragraphs 48-49) in a test sample containing the protein antigen combination, the autoantibodies and the labeled anti-human antibody (paragraph 21).
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 copending Application No. 18996523 to include on the kit the combination, purified and prepared for detecting autoantibodies, a labeled anti-human antibody that binds to the autoantibodies; and a chromogenic agent taught by Nagele because Nagele suggests this facilitates the diagnosis of Parkinson’s disease, which is a current need in the field as early detection of PD increases the quality of life of the patient. A person having ordinary skill in the art would have had a reasonable expectation of success because both copending Application No. 18996523 and Nagele teach the protein antigen combination of claim 1.
Regarding claim 11, similarly as discussed above, the particular sample which the kit is intended to be used on is specific to the intended use of the claimed kit (the sample is not a structural component of the kit itself). Nonetheless, it is noted that Nagele teaches wherein the biological sample is whole blood or serum (paragraph 20). As a result, it would be expected that the kit (combination of proteins as taught by Nagele) would similarly be capable of the intended use applied to samples as claimed.
Claims 3-4 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 11-13 and 15 of copending Application No. 18996523 in view of Nagele as applied to claim 1 above, and further in view of Rouslahti et al. (US 11571485 B2) ("Rouslahti").
Regarding claims 3-4, copending Application No. 18996523 in view of Nagele teach the protein antigen combination according to claim 1 as discussed above.
Copending Application No. 18996523 in view of Nagele fail to recite a DAG fragment shown in SEQ ID NO:5.
Rouslahti teaches “peptides and antibodies for detecting changes in Alzheimer’s disease brain and methods of use thereof” (Title). Rouslahti further teaches that “the peptide has an amino acid sequence as set forth in SEQ ID NO: 102 (CDAGRKQKC; also herein referred to as “DAG”)” (para. 25). Note that SEQ ID NO: 102 (CDAGRKQKC) is 100% matched to SEQ ID NO:5 claimed. Rouslahti also teaches that the peptide “DAG (SEQ ID NO: 102)… homed to cells in human…Parkinson's disease brain” (para. 165) and suggests the use of DAG as an imaging biomarker for Parkinson’s disease (para. 221).
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 copending Application No. 18996523 in view of Nagele to include the DAG fragment shown in SEQ ID NO:5 taught by Rouslahti because Nagele teaches that PD is a current health crisis and Rouslahti teaches that the DAG fragment shown in SEQ ID NO:5 can be used as an imaging biomarker for PD, a current health problem. A person having ordinary skill in the art would have had a reasonable expectation of success because both copending Application No. 18996523 in view of Nagele and Rouslahti are drawn to peptides related to disease detection.
Claims 5, 13-14 and 18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 11-13 and 15 of copending Application No. 18996523 in view of Nagele and Rouslahti as applied to claims 3-4 above, and further in view of Papuc, Valkirs, Coleman, Kronimus and Moe and Davidwits.
Regarding claims 5, 13-14 and 18, copending Application No. 18996523 in view of Nagele and Rouslahti teach the combination of claims 3-4 as discussed above.
Copending Application No. 18996523 in view of Nagele and Rouslahti fail to recite comprising the MAPT protein fragment shown in SEQ ID NO:1, and the HSP60 protein fragment shown in SEQ ID NO:3.
Papuc, Valkirs, Coleman, Kronimus and Moe and Davidwits are relied upon as in the 103 rejection above.
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 modify the teachings of copending Application No. 18996523 in view of Nagele and Rouslahti namely including HSP60, taught by Papuc, in the protein antigen combination, thereby arriving at the present claim, (i.e., to provide the combination of proteins together), because Valkirs et al. teach that combining makers can increase the predictive value of the analysis and both copending Application No. 18996523 in view of Nagele and Papuc teach protein antigen biomarkers of Parkinson’s disease. One would have been motivated to make such a modification in order to receive the expected benefit of diagnosing Parkinson's disease earlier, thereby slowing the progression of the disease, minimizing symptoms, and improving the overall quality of life as taught by Nagele, specifically combining the proteins together as a single product since such combination would allow for the use to detect the combination of autoantibodies, thereby increasing the predictive/diagnostic value of the product. A person having ordinary skill in the art would have had a reasonable expectation of success given that both copending Application No. 18996523 in view of Nagele and Papuc teach protein antigens for detecting Parkinson’s Disease.
It would have been further prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of copending Application No. 18996523 in view of Nagele, Rouslahti, Papuc and Valkirs et al. to rely on HSP60 shown in SEQ ID NO:3 taught by Coleman because Coleman teaches that HSP60 shown in SEQ ID NO:3 is used to diagnose Parkinson's disease. Therefore, applying the HSP60 protein fragment shown in SEQ ID NO:3 taught by Coleman to the art-recognized technique of using HSP60 as a biomarker of Parkinson’s disease taught by both Papuc and Coleman would have been obvious to a person having ordinary skill in the art. One would have been motivated to make such a modification because copending Application No. 18996523in view of Nagele teach that diagnosing PD early can increase the quality of life of the patient. A person having ordinary skill in the art would have had a reasonable expectation of success because Coleman teaches SEQ ID NO:3 in the context of neurodegenerative diseases, i.e., Parkinson’s disease, and copending Application No. 18996523 in view of Nagele, Rouslahti, Papuc and Valkirs et al. teach protein antigen combinations for detecting Parkinson’s Disease.
It would have been further prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of copending Application No. 18996523 in view of Nagele in view of Rouslahti, Papuc, Valkirs et al. and Coleman to include the MAPT protein taught by Kronimus et al. (i.e., to provide the combination of proteins together), thereby arriving at the instant claim, because Valkirs et al. teach that combining makers can increase the predictive value of the analysis and both copending Application No. 18996523 in view of Nagele and Kronimus et al. teach protein antigens to detect the related autoantibody makers shown to be associated with Parkinson’s disease. One would have been motivated to make such a modification in order to receive the expected benefit of diagnosing Parkinson's disease earlier, thereby slowing the progression of the disease, minimizing symptoms, and improving the overall quality of life as taught by Nagele, specifically combining the proteins together as a single product since such combination would allow for the use to detect the combination of autoantibodies, thereby increasing the predictive/diagnostic value of the product. A person having ordinary skill in the art would have had a reasonable expectation of success given that the 'multimarker' strategy presents a benefit with regards to risk stratification and Kronimus et al. teach MAPT autoantibody levels can identify demented vs. non-demented Parkinson’s disease patients.
It would have been further prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of copending Application No. 18996523 in view of Nagele, Rouslahti, Papuc, Valkirs et al. Coleman, and Kronimus et al., namely to rely on the SEQ. ID NO. 1 fragment taught by Moe and Davidwitz as the MAPT protein fragment, because Moe and Davidwitz teach a small, finite number of identified fragments “where tau cuts itself” (paragraph 123), thereby making it obvious for the common artisan to try one of the list of possible candidates of protein fragments related to neurodegenerative disease. There would be a reasonable expectation of success because Moe and Davidwitz disclose the molecular weight, isoelectric point and estimated charge at pH 7.4 of the protein fragment.
Claims 6, 8, 15 and 19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 11-13 and 15 of copending Application No. 18996523 in view of Nagele and Rouslahti as applied to claim 4 above, and further in view of Schmidt.
Regarding claims 6, 8, 15 and 19, copending Application No. 18996523 in view of Nagele and Rouslahti teach the combination of claims 1 and 4 as discussed above.
Nagele further teaches that Parkinson’s disease is a central nervous system disorder causing neurological damage (paragraph 2). Nagele further suggests that Parkinson’s disease is associated with myeloid malignancies (page 8). Nagele further teaches the ASXL1 protein shown in SEQ ID NO:8.
Copending Application No. 18996523 in view of Nagele and Rouslahti fail to recite the RAGE protein fragment shown in SEQ ID NO:7.
Nagele and Schmidt are relied upon as in the 103 rejection above.
It would have been further prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of copending Application No. 18996523 in view of Nagele and Rouslahti to include the ASXL1 protein shown in SEQ ID NO:8 taught by Nagele because Nagele suggests this protein as a biomarker of PD and teaches that early PD detection is crucial for PD patient's quality of life and copending Application No. 18996523 in view of Nagele, and Rouslahti teach methods and/or compositions for diagnosing Parkinson’s disease. One would have been motivated to make such a modification because work in one field of endeavor may prompt variations. In this case, the scope and content of the prior art included a similar product, i.e., a protein biomarkers of Parkinson’s disease. Given that Parkinson’s disease is an art-recognized problem, there is an incentive to adapt the base product, i.e., a protein, to include variations, namely to treat Parkinson’s disease. A person having ordinary skill in the art would have had a reasonable expectation of success because Nagele and copending Application No. 18996523 in view of Nagele and Rouslahti teach methods and/or compositions related to Parkinson’s disease and the scope of Schmidt also encompassed the use of proteins as diagnostic biomarkers.
It would have been further prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of copending Application No. 18996523 in view of Nagele and Rouslahti to include the RAGE protein fragment shown in SEQ ID NO:7 taught by Schmidt because Schmidt teaches that the RAGE protein in SEQ ID NO:7 is used to treat Parkinson's disease and copending Application No. 18996523 in view of Nagele, and Rouslahti teach methods and/or compositions for diagnosing Parkinson’s disease. One would have been motivated to make such a modification because work in one field of endeavor may prompt variations. In this case, the scope and content of the prior art included a similar product, i.e., a protein biomarkers of Parkinson’s disease. Given that Parkinson’s disease is an art-recognized problem, there is an incentive to adapt the base product, i.e., a protein, to include variations, namely to treat Parkinson’s disease. A person having ordinary skill in the art would have had a reasonable expectation of success because Schmidt and copending Application No. 18996523 in view of Nagele and Rouslahti teach methods and/or compositions related to Parkinson’s disease and the scope of Schmidt also encompassed the use of proteins as diagnostic biomarkers.
Claims 7 and 16-17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 11-13 and 15 of copending Application No. 18996523 in view of Nagele and Rouslahti as applied to claims 3-4 above, and further in view of Daffo and Riessland.
Regarding claims 7 and 16, copending Application No. 18996523 in view of Nagele and Rouslahti teach the protein combination according to claims 3-4 as discussed above.
Copending Application No. 18996523 in view of Nagele and Rouslahti fail to recite SEQ ID NO:4.
Daffo and Riessland are relied upon as in the 103 rejection above.
It would have been further prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of copending Application No. 18996523 in view of Nagele and Rouslahti to rely on the P21 protein fragment shown in SEQ ID NO:4 taught by Daffo because Daffo teaches that the P21 protein fragment shown in SEQ ID NO:4 is used to diagnose and treat Parkinson's disease and Riessland teaches that the P21 protein is associated with Parkinson’s disease. Therefore, applying the P21 protein fragment shown in SEQ ID NO:4 taught by Daffo to the art-recognized technique of using P21 for diagnosing Parkinson’s disease taught by both Daffo and copending Application No. 18996523 in view of Nagele would have been obvious to a person having ordinary skill in the art. One would have been motivated to make such a modification because Daffo teaches that the P21 protein fragment shown in SEQ ID NO:4 is also used to treat Parkinson’s disease. A person having ordinary skill in the art would have had a reasonable expectation of success because Daffo, Riessland and copending Application No. 18996523 in view of Nagele and Rouslahti teach methods and/or compositions related to Parkinson’s disease.
Regarding claim 17, copending Application No. 18996523 in view of Nagele, Rouslahti, Daffo and Riessland teach the protein antigen combination according to claim 16 as discussed above.
Copending Application No. 18996523 in view of Nagel, Rouslahti, Daffo and Riessland further teach wherein the DAG fragment has the sequence shown in SEQ ID NO:5 (para. 25 of Rouslahti).
Claim 20 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 11-13 and 15 of copending Application No. 18996523 in view of Nagele and Rouslahti as applied to claim 4 above, and further in view of Papuc, Valkirs, Coleman, Schmidt, Daffo and Riessland.
Regarding claim 20, copending Application No. 18996523 in view of Nagele and Rouslahti teach the protein combination according to claim 4 as discussed above.
Copending Application No. 18996523 in view of Nagele and Rouslahti fail to recite comprising the HSP60 protein having the sequence shown in SEQ ID NO:3, the RAGE protein fragment shown in SEQ ID NO:7, and SEQ ID NO:4.
Papuc, Valkirs, Coleman, Schmidt, Daffo and Riessland are relied upon as in the 103 rejection above.
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 modify the teachings of copending Application No. 18996523 in view of Nagele and Rouslahti namely including HSP60, taught by Papuc, in the protein antigen combination, thereby arriving at the present claim, (i.e., to provide the combination of proteins together), because Valkirs et al. teach that combining makers can increase the predictive value of the analysis and both copending Application No. 18996523 in view of Nagele and Papuc teach protein antigen biomarkers of Parkinson’s disease. One would have been motivated to make such a modification in order to receive the expected benefit of diagnosing Parkinson's disease earlier, thereby slowing the progression of the disease, minimizing symptoms, and improving the overall quality of life as taught by Nagele, specifically combining the proteins together as a single product since such combination would allow for the use to detect the combination of autoantibodies, thereby increasing the predictive/diagnostic value of the product. A person having ordinary skill in the art would have had a reasonable expectation of success given that both copending Application No. 18996523 in view of Nagele and Papuc teach protein antigens for detecting Parkinson’s Disease.
It would have been further prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of copending Application No. 18996523 in view of Nagele, Rouslahti, Papuc and Valkirs et al. to rely on HSP60 shown in SEQ ID NO:3 taught by Coleman because Coleman teaches that HSP60 shown in SEQ ID NO:3 is used to diagnose Parkinson's disease. Therefore, applying the HSP60 protein fragment shown in SEQ ID NO:3 taught by Coleman to the art-recognized technique of using HSP60 as a biomarker of Parkinson’s disease taught by both Papuc and Coleman would have been obvious to a person having ordinary skill in the art. One would have been motivated to make such a modification because copending Application No. 18996523 in view of Nagele teach that diagnosing PD early can increase the quality of life of the patient. A person having ordinary skill in the art would have had a reasonable expectation of success because Coleman teaches SEQ ID NO:3 in the context of neurodegenerative diseases, i.e., Parkinson’s disease, and copending Application No. 18996523 in view of Nagele, Rouslahti, Papuc and Valkirs et al. teach protein antigen combinations for detecting Parkinson’s Disease.
It would have been further prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of copending Application No. 18996523 in view of Nagele, Rouslahti, Papuc, Valkirs and Coleman to include the RAGE protein fragment shown in SEQ ID NO:7 taught by Schmidt because Schmidt teaches that the RAGE protein in SEQ ID NO:7 is used to treat Parkinson's disease and copending Application No. 18996523 in view of Nagele, Rouslahti, Papuc, Valkirs and Coleman teach methods and/or compositions for diagnosing Parkinson’s disease. One would have been motivated to make such a modification because work in one field of endeavor may prompt variations. In this case, the scope and content of the prior art included a similar product, i.e., a protein biomarkers of Parkinson’s disease. Given that Parkinson’s disease is an art-recognized problem, there is an incentive to adapt the base product, i.e., a protein, to include variations, namely to treat Parkinson’s disease. A person having ordinary skill in the art would have had a reasonable expectation of success because Schmidt and copending Application No. 18996523 in view of Nagele, Rouslahti, Papuc, Valkirs and Coleman teach methods and/or compositions related to Parkinson’s disease and the scope of Schmidt also encompassed the use of proteins as diagnostic biomarkers.
It would have been further prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of copending Application No. 18996523 in view of Nagele, Rouslahti, Papuc, Valkirs, Coleman and Schmidt to rely on the P21 protein fragment shown in SEQ ID NO:4 taught by Daffo because Daffo teaches that the P21 protein fragment shown in SEQ ID NO:4 is used to diagnose and treat Parkinson's disease and Riessland teaches that the P21 protein is associated with Parkinson’s disease. Therefore, applying the P21 protein fragment shown in SEQ ID NO:4 taught by Daffo to the art-recognized technique of using P21 for diagnosing Parkinson’s disease taught by both Daffo and copending Application No. 18996523 in view of Nagele would have been obvious to a person having ordinary skill in the art. One would have been motivated to make such a modification because Daffo teaches that the P21 protein fragment shown in SEQ ID NO:4 is also used to treat Parkinson’s disease. A person having ordinary skill in the art would have had a reasonable expectation of success because Daffo, Riessland and copending Application No. 18996523 in view of Nagele, Rouslahti, Papuc, Valkirs, Coleman and Schmidt teach methods and/or compositions related to Parkinson’s disease.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed 11/12/2025 have been fully considered but they are not persuasive.
Applicant argues that “the wherein clause in the previously presented claim 1 must be given patentable weight because the recited efficiency and sensitivity was more than intended result-it limits the claim to particular protein antigen combinations” (page 6 para. 5). Therefore, given that the recited efficiency and sensitivity limits the claim to particular protein antigen combinations, the particular protein antigen combination would inherently be capable of achieving the recited efficiency and sensitivity. In other words, the protein antigen combination itself inherently provides the recited specificity and sensitivity. Thus, the wherein clause fails to provide any patentable weight to the claim. Applicant further argues that “it was immaterial that the cited case law concerned wherein clause for method claims, whereas the present claims are composition claims. The wherein clause recites a condition material to patentability and must not be ignored. See Hoffer v. Microsoft Corp., 405 F.3d 1326, 1329 (Fed. Cir. 2005) (holding that when a "[wherein] clause states a condition that is material to patentability, it cannot be ignored in order to change the substance of the invention); see also MPEP 2111.04 ("Claim scope is not limited by ... claim language that does not limit a claim to a particular structure.")” (page 7 para. 1). However, as cited by Applicant, “MPEP 2111.04 ("Claim scope is not limited by ... claim language that does not limit a claim to a particular structure.")”. The wherein clause does not change the substance of the invention or impart any structure to the protein antigen combination; therefore, the wherein clause does not limit the protein antigen combination claimed. Applicant further argues that “While Cao discloses certain proteins as potential biomarkers, it focuses on full length proteins instead of fusion protein fragments for Alzheimer's disease detection” (page 7 para. 3). However, new grounds of rejection are set forth above, citing Table 2 of Cao that teaches the protein fragments claimed through their National Library of Medicine (NLM) ID number. As evidence by the NLM, the corresponding protein sequences published in their website are 100% matched to the sequences of the protein fragments claimed (see rejection above). Therefore, the claims are obvious over Cao (see rejection above). Applicant further argues that “Neither does Cao teach or suggest the protein fragment combinations (including the combination comprising SEQ ID NO:l and SEQ ID NO:2) in claim 1 can achieve overall detection sensitivity of greater than 85%. In Cao, the protein combinations comprising at least four proteins had overall detection sensitivity of 54%-83%. Cao, Table 6” (page 7 para. 4). However, as stated above, the wherein clause fails to limit the claim (see rejection above). Applicant further argues that “Parkinson's disease and Alzheimer's disease are distinct diseases… the cited prior art teaches away from using the disclosed proteins/protein fragments in Alzheimer's disease detection-Nagele discloses that the biomarkers had high overall accuracy (sensitivity and specificity) in Parkinson's disease diagnosis and was able to differentiate Parkinson's disease from other neurological or nonneurological diseases… Yet Examiner relies on Parkinson's disease-focused prior art to formulate rejections, including the motivation to combine arguments, while the present invention focuses on Alzheimer's disease detection. This reliance is misplaced. A person of ordinary skill would not have been motivated to combine these disparate teachings to arrive at the specific protein fragment combinations recited in the present claims, particularly given the unpredictability in the field of Alzheimer's disease diagnostics and the lack of guidance for selecting the specific fragments claimed in the cited prior art” (page 8 para. 3-6 and page 9 para. 1). However, although the analysis relies on the application of the protein antigen combination to detect Parkinson’s disease and not Alzheimer’s disease, given that the claims are to the protein antigen combination and not to a method of diagnosing Alzheimer’s disease, the limitations drawn to the detection of Alzheimer’s disease are not required in order to address the claim. The protein antigen combination taught by the prior art would inherently be capable of achieving the same outcomes as the protein antigen combination claimed because they are structurally equivalent, they are made up of the same amino acid sequence and therefore have the same functional capabilities.
Conclusion
No claim is allowed.
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/Fernando Ivich/ Examiner, Art Unit 1678
/CHRISTOPHER L CHIN/ Primary Examiner, Art Unit 1677