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.
Status of the Claims
Claims 1-5, 8-12, 35, 36, have been amended. Claims 15-34 have been canceled. Claims 1-14, 35-38, 42, and 43 are pending and examined herein.
Priority
This application, 18/835,014, filed 07/31/2024, is a 371 of PCT/US2023/061703 filed on 01/31/2023, and claims benefit of provisional application 63/395,289 filed on 08/04/2022. This priority is acknowledged and the claims examined herein are treated as having an effective filing date of 08/04/2022.
Information Disclosure Statement
The Information Disclosure Statement filed on 07/31/2024 is acknowledged and has been considered.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 8, 9, 11-14, 35-38 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 8 recites “…based on elevated levels of expression …”. The recitation of “elevated” is relative terminology, and as such the claim is indefinite because it is not readily clear compared to what standard is it being compared to be considered elevated.
Claim 14 recites “…wherein the senescence-associated disease or disorder is one or more of…neurogenesis…”. The claim is indefinite because it is unclear how neurogenesis itself could be considered a senescence-associated disease or disorder, as one of ordinary skill in the art would recognize that neurogenesis is a process that occurs in healthy human subjects. While a decline in neurogenesis may be correlated with senescence-associated diseases or disorders, the application disclosure provides no teaching of when neurogenesis can be considered a senescence-associated disease or disorder. Therefore, the claim is indefinite because there are multiple possible conflicting interpretations based on the claim language provided. For example, it is unclear if the claim language is to be interpreted as a decrease/absence of neurogenesis is considered to be a senescence-associated disease or disorder, or alternatively, whether an increase neurogenesis is considered to be a senescence-associated disease or disorder. As there are multiple potential conflicting interpretations of the claim language, this claim is indefinite.
Appropriate correction is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-14 and 35-38 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exceptions without significantly more.
Claim 1 recites “A method of distinguishing non-senescent cells from senescent cells, the method comprising a step of comparing levels of one or more biomarkers from the non-senescent cells and senescent cells wherein the biomarkers are comprised of proteins selected from LYAG, TPP1 and LAMP-1”.
Claim 8 recites “A method of detecting an ailment or determining a prognosis of an ailment, the method comprising a) detecting levels of one or more biomarkers in a sample from a test subject, b) identifying the ailment or determining the prognosis of the ailment based on elevated levels of expression of the one or more biomarkers in the sample, and c) treating the subject with a senolytic agent to prevent or ameliorate the ailment, wherein the ailment is a senescence-associated disease or disorder, wherein the biomarkers are comprised of proteins selected from LYAG, TPP1 and LAMP-1.
The claims are directed to judicial exceptions, mainly they are abstract ideas, specifically, mental processes that can be performed in the human mind, and/or are merely observing naturally occurring correlations (laws of nature/natural correlation). These judicial exceptions are not integrated into a practical application because there is no practical application recited in the claims such as performing a treatment in a way that is particular, and not merely instructions to "apply" the exception in a generic way. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional steps amount to mere data gathering that does not go beyond well-understood, routine, and conventional activity; as detailed below.
Step 1 – Whether a claim is to a statutory category - YES
The instantly claimed invention is directed to a method of distinguishing non-senescent cells from senescent cells, and a method of detecting an ailment or determining a prognosis of an ailment. Therefore, the instantly claimed invention falls into one of the four statutory categories.
Step 2A Prong 1 – Whether the claim is directed to a judicial exception (i.e. Does the claim recite an abstract idea, law of nature, or natural phenomenon?) - YES
Claims 1 and 8 recite the following steps which fall under the mental processes grouping of abstract ideas and/or laws of nature/natural correlation:
Claim 1 discloses a method of distinguishing non-senescent cells from senescent cells by “comparing” levels of one or more of the LYAG, TPP1 and LAMP-1 biomarkers from the non-senescent cells and senescent cells. Claim 8 discloses a method for detecting an ailment or “determining” a prognosis of an ailment based on elevated levels of expression of one or more of the LYAG, TPP1 and LAMP-1 biomarkers in a sample.
These limitations of claim 8 recite a law of nature which is a judicial exception, because it is merely observing the correlation between naturally occurring biomarkers (LYAG, TPP1 and LAMP-1) and its relationship to an disease/disease state (senescence-associated disease/disorder), and using these levels to make a determination of a subjects’ disease state, which are abstract ideas, specifically, abstract mental processes
The “determining” steps can be regarded as a law of nature, namely, the naturally occurring correlation between biomarker expression level and disease state (senescence-associated disease/disorder). Regarding the identification of a correlation between the presence of a biomarker in a bodily sample and disease state the courts have held similar claims to be laws of nature and/or natural phenomena, as in Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1361, 123 USPQ2d 1081, 1087 (Fed. Cir. 2017) which involved claims to simply instruct a user to apply a natural law, by correlating naturally occurring enzyme levels with disease risk. In Mayo, the Supreme Court found that a claim was directed to a natural law, where the claim required administering a drug and determining the levels of a metabolite following administration, where the level of metabolite was indicative of a need to increase or decrease the dosage of the drug. See Mayo Collaborative Services V. Prometheus Labs., Inc., 566 U.S. 66, 74 (2012). The instant claims are similar to those in Mayo as they involve a "relation itself [which] exists in principle apart from any human action" (id. at 77). Claims 8-14 and 35-38 do not recite administering a specific treatment and instructions to "apply" the exception in a way that is not generic (discussed further below). While some claims could be considered to recite a specific treatment (claims 13 and 38), the instructions to "apply" are generic, because as recited the administration of the treatment does not depend upon the levels of biomarker expression.
Regarding the steps in claims 1-7 reciting a step of “comparing” levels of one or more of the LYAG, TPP1 and LAMP-1 protein biomarkers from the non-senescent cells and senescent cells, the courts have held similar claims to be abstract mental processes, as in University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 763, 113 USPQ2d 1241, 1246 (Fed. Cir. 2014) which involved claims to "comparing BRCA sequences and determining the existence of alterations," where the claims cover any way of comparing BRCA sequences such that the comparison steps can practically be performed in the human mind. The claims are also similar to that in Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1067, 100 USPQ2d 1492, 1500 (Fed. Cir. 2011), which involved a claim to “collecting and comparing known information” (both of these court cases are discussed in MPEP 2106.04(a)(2) (II)(A)). The steps of “determining” and “distinguishing” (claims 1-14, 35-38) also constitutes an abstract mental process, involving assessing the levels of the biomarkers in the sample, and then making an evaluation or judgment as to whether a cell is non-senescent or senescent, or making an evaluation or judgment as to the presence of a disease or the severity/state of a test subjects’ particular disease (senescence-associated disease) based on that detection. The comparison and “determining”/”distinguishing” steps could be performed in the human mind, or by a human using pen and paper, insofar as it reads on comparing levels and drawing conclusions from this about the health status of a subject.
Thus, claims 1-14 and 35-38 fall into a judicial exception.
Step 2A: Prong 2 - Does the claim recite additional elements that integrate the judicial exception into a practical application? The Step 2A, Prong 2 analysis requires identifying whether there are any additional elements recited in the claim beyond the judicial exception(s), and evaluating those additional elements to determine whether they integrate the exception into a practical application of the exception.
Claims 1-14 and 35-38 do not recite any additional element that integrate the exception into a practical application of the exception. The additional step in these claims of treating the subject with a senolytic agent to prevent or ameliorate the ailment, is insufficient to integrate the exception into a practical application because the purpose is merely to obtain data and/or merely instructions to "apply" the exception in a generic way. MPEP 2106.04(d)(2) states, the treatment or prophylaxis limitation must be “particular”, i.e., specifically identified so that it does not encompass all applications of the judicial exception(s), for it to integrate the judicial exception. While some claims could be considered to recite a specific treatment recite a specific treatment (claims 13 and 38), the instructions to "apply" are generic, because as recited the administration of the treatment does not depend upon the levels of biomarker expression (e.g. treatment choice is not determined based on expression level direction).
Regarding dependent claims 2-7, 9-14, and 35-38, they do not recite any additional elements that integrate the judicial exception into a practical application. The additional steps of measuring expression of additional biomarkers (claims 2-5, 9-12), labeling and removing senescent cells (claims 6 and 7), using a senolytic agent inhibits lysosomal exocytosis (claim 13), specifying the senescence-associated disease or disorder (claim 14), assessing the efficacy of the senolytic agent (claim 35), and treating using a drug conjugate (claims 36-38), are insufficient to integrate the exception into a practical application because the purpose is merely to obtain data to observe a naturally occurring correlation and/or perform a mental process.
As in In re Grams, 888 F.2d 835, 839-40; 12 USPQ2d 1824, 1827-28 (Fed. Cir. 1989), such activity involving performing clinical tests on individuals constitutes mere data gathering, and does not go beyond insignificant extra-solution activity. See MPEP §§ MPEP 2106.04(d)(I) and 2106.05(g). There are no subsequent steps recited after the “determining” or comparison steps that would practically apply the method depending on the results of the measurements, e.g., specific treatment and non-generic instructions or other process steps that are performed after the test subject has been diagnosed with a disease.
In particular, of the claims indicated in the rejection heading, none of the additionally recited limitations amount to an additional element or combination of elements that apply, rely on, or use the judicial exceptions in a manner that impose meaningful limit on the judicial exceptions.
Step 2B; Whether the additional elements contribute an “inventive concept”. In the second step it is determined whether the claimed subject matter includes additional elements that amount to significantly more than the judicial exception. See MPEP 2106.05.
Briefly, claims 1-14 and 35-38 do not include additional elements that are sufficient to amount to significantly more than the judicial exception because of the following reasons. Simply appending well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, has been found to be insufficient to add “significantly more” (MPEP 2106.05(I)(A)).
The additional steps recited above do not add a meaningful limitation to the instant method as they would have been routinely used by those of ordinary skill in the art as supported by Kim et al. (2017). “Identification of senescent cell surface targetable protein DPP4”. Genes & development, 31(15), 1529-1534, (herein referred to as Kim), Annunziata et al. (US20200087704A1), (herein referred to as Annunziata), Poblocka et al. (2021). “Targeted clearance of senescent cells using an antibody-drug conjugate against a specific membrane marker”. Scientific reports, 11(1), 20358, (herein referred to as Poblocka), and Guangzhou Institute of Biomedicine and Health et al. (CN113521078A), (herein referred to as GBH).
Kim teaches mass spectrometry analysis revealed that DPP4 (dipeptidyl peptidase 4) was selectively expressed on the surface of senescent, but not proliferating, human diploid fibroblasts (abstract). Kim teaches that importantly, the differential presence of DPP4 allowed flow cytometry-mediated isolation of senescent cells using anti-DPP4 antibodies, and moreover, antibody-dependent cell-mediated cytotoxicity (ADCC) assays revealed that the cell surface DPP4 preferentially sensitized senescent, but not dividing, fibroblasts to cytotoxicity by natural killer cells (abstract). Kim teaches that they fractionated membrane-associated proteins and cell surface-associated proteins as described (Materials and Methods) and surveyed them by MS analysis (see Supplemental Table S1 for complete MS data set) (page 1529, column 2, 4th paragraph). Kim teaches that they focused on the proteins that were more abundant among membrane proteins (a fraction that included endoplasmic reticulum, mitochondria, and other intra cellular membrane structures) and among cell surface proteins in senescent compared with proliferating fibroblasts (page 1530, column 1, 1st paragraph). Kim teaches in Supplemental Table S1 the measurement of LYAG, TPP1 and LAMP-1 proteins.
Annunziata teaches methods for the prognosis, diagnosis and treatment of various pathological states, including cancer, chemotherapy resistance and dementia associated with Alzheimer's disease (abstract). Annunziata teaches that the methods provided herein are based on the discovery that various proteins with a high level of sialylation are shown herein to be associated with disease states, such as, cancer, chemotherapy resistance and dementia associated with Alzheimer's disease, and such methods provide a lysosomal exocytosis activity profile comprising one or more values representing lysosomal exocytosis activity (abstract). Annunziata teaches that by “lysosomal exocytosis activity profile” is meant a profile of one or more values representing lysosomal exocytosis activity, and as used herein, “lysosomal exocytosis activity” is meant a measure of the level of exocytosis in a sample. Annunziata teaches that various markers can be used to determine the lysosomal exocytosis activity of a sample, and that such markers include one or more of the following: (1) the level of NEU1 protein or direct enzymatic activity of NEU1; (2) the protein level of one or more NEU1 substrates; (3) the protein level of one or more lysosomal proteins; (4) the protein level of one or more lysosomal proteases; (5) the protein level of LAMP-1; (6) the protein level of hexosaminidase beta; (7) the protein level of mannosidase alpha (MA2B1); or (8) the protein level of one or more cathepsins; (9) any marker for a sialylation activity profile provided herein; or (10) any marker for a lysosomal sialidase activity profile provided herein ([0016]).
Poblocka teaches the targeted clearance of senescent cells using an antibody-drug conjugate against a specific membrane marker (title). Poblocka teaches the use of an extracellular epitope of B2M, a recently identified membrane marker of senescence, as a target for the specific delivery of toxic drugs into senescent cells, and shows that an antibody–drug conjugate (ADC) against B2M clears senescent cells by releasing duocarmycin into them, while an isotype control ADC was not toxic for these cells (abstract). Poblocka teaches that this effect was dependent on p53 expression and therefore more evident in stress-induced senescence, and that non-senescent cells were not affected by either antibody, confirming the specificity of the treatment (abstract). Poblocka also teaches that the prior senolytics tested so far lack specificity and have significant off-target effects, suggesting that a targeted approach could be more clinically relevant because a more specific strategy would be desirable in order to reduce the side effects and increase the efficiency of these drugs (abstract).
GBH teaches a senescent cell killing agent and its application (abstract). GBH teaches The senescent cell killing agent comprises apilimod or a pharmaceutically acceptable salt, ester or solvate thereof, and that the present invention discovers for the first time that the drug Apilimod has a specific killing effect on aging cells, and the killing rate is above 70%, so it can be used as a new type of aging cell killing agent, because it can efficiently remove aging cells, more likely as a potential new anti-aging drug (abstract). GHB teaches that apilimod has no damage to non-aged cells, so the medicine can be used as a novel aged cell killing agent, and can be more likely to be used as a potential novel anti-aging medicine because the medicine can efficiently remove the aged cells ([0024]). GHB teaches that preferably, the dosage form of the aged cell killing agent comprises tablets, suspensions, disintegrants, capsules, granules, powders, emulsions, injections, sprays, films, suppositories, nasal drops or dropping pills ([0016]).
Therefore, the instantly rejected claims are not drawn to eligible subject matter as they are directed to a law of nature and abstract idea without significantly more. For additional guidance, applicant is directed generally to MPEP § 2106.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-7 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kim et al. (2017). “Identification of senescent cell surface targetable protein DPP4”. Genes & development, 31(15), 1529-1534, (herein referred to as Kim).
Regarding claim 1, Kim teaches mass spectrometry analysis revealed that DPP4 (dipeptidyl peptidase 4) was selectively expressed on the surface of senescent, but not proliferating, human diploid fibroblasts (abstract). Kim teaches that importantly, the differential presence of DPP4 allowed flow cytometry-mediated isolation of senescent cells using anti-DPP4 antibodies, and moreover, antibody-dependent cell-mediated cytotoxicity (ADCC) assays revealed that the cell surface DPP4 preferentially sensitized senescent, but not dividing, fibroblasts to cytotoxicity by natural killer cells (abstract). Kim teaches that they fractionated membrane-associated proteins and cell surface-associated proteins as described (Materials and Methods) and surveyed them by MS analysis (see Supplemental Table S1 for complete MS data set) (page 1529, column 2, 4th paragraph). Kim teaches that they focused on the proteins that were more abundant among membrane proteins (a fraction that included endoplasmic reticulum, mitochondria, and other intra cellular membrane structures) and among cell surface proteins in senescent compared with proliferating fibroblasts (page 1530, column 1, 1st paragraph). Kim teaches in Supplemental Table S1 the measurement of LYAG, TPP1 and LAMP-1 proteins.
Regarding claims 2-5, Kim teaches the measurement of CO8A1, CATC, IBP7, and DPP4 (Supplemental Table S1).
Regarding claims 6 and 7, Kim teaches that they carried out ADCC analysis using increasing concentrations of anti-DPP4 antibody (up to 5 µg/mL) to bind the DPP4 surface marker and thereby label proliferating and senescent WI-38 fibroblasts. Kim teaches that they then isolated NK cells from human PBMCs and added them to the WI-38 cultures, allowing the NK cells to destroy the cells labeled by anti-DPP4 antibody (page 1532, column 2, 1st paragraph).
Claims 8, 10-14, and 42 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Annunziata et al. (US20200087704A1), (herein referred to as Annunziata).
Regarding claim 8, Annunziata teaches methods for the prognosis, diagnosis and treatment of various pathological states, including cancer, chemotherapy resistance and dementia associated with Alzheimer's disease (abstract). Annunziata teaches that the methods provided herein are based on the discovery that various proteins with a high level of sialylation are shown herein to be associated with disease states, such as, cancer, chemotherapy resistance and dementia associated with Alzheimer's disease, and such methods provide a lysosomal exocytosis activity profile comprising one or more values representing lysosomal exocytosis activity (abstract). Annunziata teaches that by “lysosomal exocytosis activity profile” is meant a profile of one or more values representing lysosomal exocytosis activity, and as used herein, “lysosomal exocytosis activity” is meant a measure of the level of exocytosis in a sample. Annunziata teaches that various markers can be used to determine the lysosomal exocytosis activity of a sample, and that such markers include one or more of the following: (1) the level of NEU1 protein or direct enzymatic activity of NEU1; (2) the protein level of one or more NEU1 substrates; (3) the protein level of one or more lysosomal proteins; (4) the protein level of one or more lysosomal proteases; (5) the protein level of LAMP-1; (6) the protein level of hexosaminidase beta; (7) the protein level of mannosidase alpha (MA2B1); or (8) the protein level of one or more cathepsins; (9) any marker for a sialylation activity profile provided herein; or (10) any marker for a lysosomal sialidase activity profile provided herein ([0016]). Annunziata teaches that NEU1 is a regulator of lysosomal exocytosis, and that moreover, NEU1 is the only known regulator of lysosomal exocytosis, and that defects in lysosomal exocytosis have been associated with various diseases ([0067]).
Annunziata teaches methods of treating a subject having a cancer or having dementia associated with Alzheimer's disease by administration of a therapeutically effective amount of NEU1 or an active variant or fragment thereof, administration of a therapeutically effective amount of protective protein/cathepsin A (PPCA) or an active variant or fragment thereof or administration of a therapeutically effective amount of a combination of NEU1 and PPCA to a subject that has cancer or dementia associated with Alzheimer's disease, where the purpose is to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect the condition or the symptoms of the cancer or dementia associated with Alzheimer's disease ([0105]).
Regarding claims 10-12, Annunziata teaches measuring the protein level of mannosidase alpha (MA2B1) ([0016]).
Regarding claims 13, 14, and 42, Annunziata teaches methods of treating a subject having a cancer or having dementia associated with Alzheimer's disease (senescence-associated disease) by administration of a therapeutically effective amount of NEU1 which inhibits lysosomal exocytosis ([0067]; [0105]).
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 9 is rejected under 35 U.S.C. 103 as being unpatentable over Annunziata as applied to claim 8 above, in view of Kim, as evidenced by Kos et al. (01/03/2022). “Lysosomal peptidases—intriguing roles in cancer progression and neurodegeneration”. FEBS Open Bio, 12: 708-738, (herein referred to as Kos).
The teachings of Annunziata and Kim are incorporated herein.
Regarding claim 9, Annunziata teaches all the limitations of claim 8 of the instant application, and also teaches that in their method the protein in a sample can be quantitatively measured by a variety of assays utilizing antibodies for a specific protein, such as immunoassays, radioimmunoassays, enzyme-linked immunosorbant assays and two-antibody sandwich assays, and also that quantitative western blotting can also be used to determine the level of protein ([0036]). Annunziata also teaches that the prognosis of a disease or pathological condition in a subject can be greatly improved with an early diagnosis, but that reliable prognostic and diagnostic methods are lacking for managing disease states ([0005]). Annunziata teaches that for example, for Alzheimer's disease, the only definitive diagnostic test is to determine whether amyloid plaques are present in a subject's brain tissue, a determination that can only be made after death and thus, due to the lack of suitable diagnostic methods only a tentative diagnosis can be provided ([0005]).
However, Annunziata does not teach wherein the one or more biomarkers are further comprised of proteins selected from CO8A1, CATC, and IBP7.
Kim teaches the measurement of CO8A1, CATC, IBP7, and DPP4 (Supplemental Table S1). Kim also teaches the measurement of CATB, CATD, and PPCA.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the methods for the prognosis, diagnosis and treatment of various pathological states by measuring various biomarkers as taught by Annunziata, to further include measuring CO8A1, CATC, or IBP7, as taught by Kim, because Annunziata teaches that their method that measures lysosomal exocytosis activity provides the advantage of a diagnosis and prognosis of pathological conditions such as Alzheimer’s which have no definitive tests premortem. Kim teaches the measurement of cell surface proteins, including CATC, in order to determine markers of senescent cells and act as therapeutic targets, because such senescent cell accumulation is linked to age-associated diseases. Additionally, lysosomal peptidases such as cathepsins have been identified as hallmarks of aging and neurodegeneration, and CatC is also involved in autophagic turnover by inducing endoplasmic reticulum stress and apoptosis, as evidenced by Kos (page 714, column 1, 2nd paragraph). Therefore, it would have been obvious to use the method of Annunziata to additionally measure CATC along with LAMP-1, in order to improve the diagnostic/prognostic sensitivity of the method outcomes by measuring an additional biomarker for determining lysosomal exocytosis activity in order to improve patient outcomes and inform treatment decisions. A person of ordinary skill would have had a reasonable expectation of success in modifying the method of Annunziata, because Annunziata already teaches measuring cathepsins in their method (CATB, CATD, and PPCA), and also that a variety of assay types can be used to quantify cathepsins such as ELISA and Western blots, which are well-understood, routine, and conventional activities in the field of protein measurement.
Claim 35 is rejected under 35 U.S.C. 103 as being unpatentable over Annunziata as applied to claim 8 above.
The teachings of Annunziata are incorporated herein.
Regarding claim 35, Annunziata teaches all the limitations of claim 8 of the instant application, and also teaches assessing the efficacy of the senolytic agent ([0107]), and frequent administrations of relatively large doses of bioactive compounds may be required to sustain therapeutic efficacy ([0119]). Annunziata also teaches that there is a need for diagnostic and prognostic tests to predict the efficacy of a particular chemotherapy regime to determine the best treatment options for a subject ([0005).
However, Annunziata does not specifically teach repeating steps a, b, and c, after administering the treatment.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the methods for the prognosis, diagnosis and treatment of various pathological states by measuring various biomarkers as taught by Annunziata, to repeat steps a, b, and c, after administering the treatment, as it would be “obvious to try”. Annunziata teaches the importance and need for the ability to determine the efficacy of a given treatment. Therefore, it would have been obvious to a person of ordinary skill in the art to repeat steps a, b, and c, after administering the treatment in order to determine the efficacy in order to make an informed decision as to whether the treatment should be continued/discontinued or whether a change should be made to the dosage or treatment type. A person of ordinary skill would have been motivated to make this modification in order to determine the best treatment options and course of action for the patient’s care in order to improve health outcomes and/or improve quality of life. A person of ordinary skill would have had a reasonable expectation of success in making this modification because it is merely repeating the steps already taught by Annunziata, and there are no limitations in the method of Annunziata that would prevent the repetition.
Claims 36, 37, and 38 are rejected under 35 U.S.C. 103 as being unpatentable over Annunziata as applied to claim 8 above, in view of Poblocka et al. (2021). “Targeted clearance of senescent cells using an antibody-drug conjugate against a specific membrane marker”. Scientific reports, 11(1), 20358, (herein referred to as Poblocka).
The teachings of Annunziata are incorporated herein.
Regarding claims 36, 37, and 38, Annunziata teaches all the limitations of claim 8 of the instant application, and also teaches the administration of an antibody against the LAMP-1 binding site so that it cannot facilitate lysosomal movement ([0218]), and that this antibody was commercially available ([0265]).
However, Annunziata does not teach that the step of treating the subject comprises administering a drug conjugate to the subject, wherein the drug conjugate comprises (a) a senescent cell targeting agent configured to target and bind to the at least one senescent cell biomarker and (b) a cytotoxic agent, which kills the bound senescent cell. Annunziata also does not teach that the targeting agent is an antibody or an antigen binding fragment thereof, an aptamer, a plastic antibody or a small molecule.
Poblocka teaches the targeted clearance of senescent cells using an antibody-drug conjugate against a specific membrane marker (title). Poblocka teaches the use of an extracellular epitope of B2M, a recently identified membrane marker of senescence, as a target for the specific delivery of toxic drugs into senescent cells, and shows that an antibody–drug conjugate (ADC) against B2M clears senescent cells by releasing duocarmycin into them, while an isotype control ADC was not toxic for these cells (abstract). Poblocka teaches that this effect was dependent on p53 expression and therefore more evident in stress-induced senescence, and that non-senescent cells were not affected by either antibody, confirming the specificity of the treatment (abstract). Poblocka also teaches that the prior senolytics tested so far lack specificity and have significant off-target effects, suggesting that a targeted approach could be more clinically relevant because a more specific strategy would be desirable in order to reduce the side effects and increase the efficiency of these drugs (abstract). Poblocka teaches that ADCs for targeted treatment has been intensively explored to design novel therapies for a range of diseases (page 2, 3rd paragraph). Poblocka teaches that ADCs have showed higher efficacy than unconjugated antibodies and have already been approved for the treatment of cancers such as relapsed Hodgkin and systemic anaplastic large cell lymphomas and many others are undergoing clinical trials, thus making them a clinically relevant tool (page 2, 3rd paragraph). Poblocka teaches that the B2M ADC could be particularly useful to clear the senescent cells that arise after chemo/radiotherapy, a form of SIPS, which are suspected to be involved in tumour resistance and relapse, and that others could be tailored to address issues related to accumulation of cells due to replicative senescence, which play an important role in age-related pathologies, by using a different epitope (page 6, 3rd paragraph). Poblocka also teaches that if necessary, cytotoxic stimuli that require the presence of more than one target on the cell surface could be designed (for instance, a toxic payload divided in two essential parts, which could be delivered into cells using ADCs against two different markers), which would greatly reduce the potential toxic side effects while increasing their specificity and thus increasing the feasibility of the approach (page 6, 3rd paragraph). Poblocka teaches that conjugation of reagents to a monoclonal (mAb) IgG1 B2M Antibody (LifeSpan BioSciences, #LS-B2200) and IgG1 Isotype (non-binding) mAb was performed by adding tris(2-car boxyethyl)phosphine (TCEP) to a solution of the antibodies (page 7, 6th paragraph).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the methods for the prognosis, diagnosis and treatment of various pathological states by measuring various biomarkers as taught by Annunziata, to administer a drug conjugate comprising a senescent cell targeting antibody and a cytotoxic agent which kills the bound senescent cell, due to the many advantages of the antibody-drug conjugate system taught by Poblocka. For example, Poblocka teaches that ADCs for targeted treatment have already been intensively explored to design novel therapies for a range of diseases, show higher efficacy than unconjugated antibodies, have already been approved for the treatment of cancers, and could be modified to target more than one cell surface marker to increase specificity and decrease side effects. A person of ordinary skill would have had a reasonable expectation of success in making this modification because Annunziata already teaches the administration of an antibody against a surface senescent cell biomarker, in both methods commercially available antibodies were used, and Poblocka teaches a method of how to synthesize an ADC using such a commercial antibody (page 7, 6th paragraph).
Claim 43 is rejected under 35 U.S.C. 103 as being unpatentable over Annunziata as applied to claim 8 above, in view of Guangzhou Institute of Biomedicine and Health et al. (CN113521078A), (herein referred to as GBH).
The teachings of Annunziata are incorporated herein.
Regarding claim 43, Annunziata teaches all the limitations of claim 42 of the instant application, and also teaches that the senolytic agent in their method can be administered via various methods, compositions, and dosages ([0121]-[0124]).
However, Annunziata does not teach wherein the senolytic agent is vacuolin-1 or apilimod.
GBH teaches a senescent cell killing agent and its application (abstract). GBH teaches The senescent cell killing agent comprises apilimod or a pharmaceutically acceptable salt, ester or solvate thereof, and that the present invention discovers for the first time that the drug Apilimod has a specific killing effect on aging cells, and the killing rate is above 70%, so it can be used as a new type of aging cell killing agent, because it can efficiently remove aging cells, more likely as a potential new anti-aging drug (abstract). GHB teaches that apilimod has no damage to non-aged cells, so the medicine can be used as a novel aged cell killing agent, and can be more likely to be used as a potential novel anti-aging medicine because the medicine can efficiently remove the aged cells ([0024]). GHB teaches that preferably, the dosage form of the aged cell killing agent comprises tablets, suspensions, disintegrants, capsules, granules, powders, emulsions, injections, sprays, films, suppositories, nasal drops or dropping pills ([0016]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the methods for the prognosis, diagnosis and treatment of various pathological states as taught by Annunziata, to use apilimod as the senolytic agent administered, as taught by GHB, as a matter of simple substitution. Annunziata already teaches administering a therapeutic amount of a senolytic agent that inhibits lysosomal exocytosis similar to apilimod as taught by GHB, and also teaches that in their method the therapeutically effective treatment can be administered via various methods, compositions, and dosages. Therefore, it would have been a matter of simple substitution to substitute the treatment of Annunziata with apilimod, and a person of ordinary skill would have been motivated to make this modification because GHB teaches that apilimod can efficiently remove senescent cells without damaging non-senescent cells, reducing off target damage and potentially improving patient quality of life and/or treatment outcomes. A person of ordinary skill would have had a reasonable expectation of success in modifying the method of Annunziata, because both references teach the use senolytic agents that can be administered in various forms, and because apilimod is an effective senolytic agent that is commercially available as taught by GHB.
Conclusion
For all the reasons discussed above, claims 1-14, 35-38, 42, and 43 are rejected and therefore no claims are allowed.
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/ALEXANDER J. HOFFMAN/ Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 October 12, 2026
