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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 June 27, 2025 has been entered.
DETAILED ACTION
The instant application is a US national phase of PCT/US2020/016549, filed February 4, 2020 and has provisional application 62/800944, filed February 4, 2019.
Applicant’s amendment filed June 27, 2025 is acknowledged. Claims 11-12, 20, and 22-26 are canceled, and claims 1, 10, 14, 19, 21, 27, and 30 are amended. Currently claims 1-10, 13-19, 21, and 27-31 are pending and under examination.
The previous 112(a) rejection and 112(b) rejection in the Final office action mailed December 27, 2024 are withdrawn due to Applicant’s amendment to the claims filed June 27, 2025.
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 1-10, 13-19, 21, and 27-31 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of improving cognitive function comprising administering/introducing a glycan-specific phospholipase D1 (Gpld1) that comprises a region having at least 95% identity to amino acid positions 24-840 according to SEQ ID NO: 1, wherein the Gpld1 is administered systemically to an individual at least 50 years old with age-related cognitive decline, does not reasonably provide enablement for a method of improving cognitive function comprising administering/introducing a Gpld1 that comprises a region having at least 95% identity to amino acid positions 24-840 according to SEQ ID NO: 1, wherein the Gpld1 is administered locally to the brain to any aged individual. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The following factors have been considered in the analysis of enablement: (1) the breadth of the claims, (2) the nature of the invention, (3) the state of the prior art, (4) the level of one of ordinary skill, (5) the level of predictability in the art, (6) the amount of direction provided by the inventor, (7) the existence of working examples, (8) the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The breadth of the claims:
Claims 1-10, 13-19, 21, and 27-31 are drawn to a method for improving cognitive function in an individual by administering an effective amount of phosphatidylinositol-glycan-specific phospholipase D1 (GPLD1) comprising a region having at least 95% identity to amino acid positions 24-840 according to SEQ ID NO: 1, wherein the Gpld1 is administered systemically or locally to the brain, as well as introducing expression constructs encoding said Gpld1 or introducing genetically modified hepatocytes expressing said Gpld1 into an individual.
The nature of the invention:
The nature of the invention relies upon administering either systemically or locally to the brain, the GPLD1 to improve cognitive function in any aged individual, thereby improving cognitive function.
The state of the prior art:
A thorough review of the patent and non-patent literature indicates that the state of the art demonstrating improving cognitive function to an individual with a composition congruent with the invention is lacking.
Contradictory evidence in the prior art for the role GPI-PLD plays in chronic diseases as reviewed by Cao et al. (J Cell Physiol. 2023;238:1407–1415, cited in PTO-892 mailed 12/27/2024) discloses the gene of GPLD1 is found to sharply increase in highly malignant tumor, indicating that GPLD1 expression might be closely associated with tumor malignancy, which is a disorder identified in the Specification associated with an individual having a symptom of cognitive decline (pg. 1410, sec. 4.2). Cao et al. also discloses increased expression of GPI-PLD is associated with neurodegenerative disorders such as multiple schizophrenia and autism spectrum disorder (pg. 1412, Table 1). Cao discloses that increasing systemic concentration of GPLD1 in aged mice can alleviate aging‐related regenerative and cognitive impairments by altering signaling cascade cleavage of downstream GPI-anchored substrates (pg. 1412, col. 1, para 2). Cao also discloses in humans serum, GPLD1 activity appears to be influenced by multiple elements including age, inter alia (pg. 1409, col. 1, para 2). Klein (Journal of Neurochemistry, 2005, 94, 1473–1487) also discloses GPI-PLD implications in neurodegeneration, and suggest a protective role of PLD in neurodegeneration, e.g. in Alzheimer’s disease, however Klein points out it is not known whether PLD activation is part of a pathological cascade in Alzheimer’s disease or part of a cellular rescue program (pg. 1479, col 1-2).
Thus, a review of the prior art does not find a correlation between administering locally to the brain GPLD1 to any aged individual, thereby improving cognitive function.
The level of one of ordinary skill:
While the level of one of ordinary skill practicing said invention would be high, the level of predictability is considered variable as evident in the prior art discussed above and is not considered to provide sufficient enablement to practice the claimed invention. Because the state of the prior art does not provide evidence of the degree of predictability that methods for improving cognitive function in any aged individual with administering GPLD1, one of ordinary skill in the art would look for guidance or direction in the instant specification.
The level of predictability in the art:
“The “predictability or lack thereof” in the art refers to the ability of one skilled in the art to extrapolate the disclosed or known results to the claimed invention. If one skilled in the art can readily anticipate the effect of a change within the subject matter to which the claimed invention pertains, then there is predictability in the art. On the other hand, if one skilled in the art cannot readily anticipate the effect of a change within the subject matter to which that claimed invention pertains, then there is lack of predictability in the art. Accordingly, what is known in the art provides evidence as to the question of predictability.” (MPEP 2164.03). As seen in the above cited prior art, the levels of GPLD1 in diseased individuals with MS or mutations in the GPI-PLD related metabolic pathway does not correlate, and the beneficial levels of GPLD1 (whether being increased or suppressed) is variable and unpredictable depending on the type of disease/dysfunction treated. Further as stated in the Specification, adult neurogenesis in humans remains controversial (para 102).
The amount of direction provided by the inventor:
The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The “amount of guidance or direction” refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling. >See, e.g., Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1326 (Fed. Cir. 2004).
The existence of working examples:
The working embodiments in the instant application describes increasing GPLD1 levels through exercise and administration of aged exercise plasma (AEP) to aged mice systemically. The aged mice administered with the AEP showed improved learning and memory compared to sedentary aged mice plasma. GPLD1 was identified as being increased in the AEP, and when overexpressed in the liver, changed the hippocampus and improved cognitive testing performance of the aged mice. Human GPLD1 levels were assessed between sedentary and active elderly adults, and were seen to be significantly elevated in the active adults. While the MPEP 2164.02 states the specification need not contain an example if the invention is otherwise disclosed in such manner that one skilled in the art will be able to practice it without an undue amount of experimentation. In re Borkowski, 422 F.2d 904, 908, 164 USPQ 642, 645 (CCPA 1970), the lack of a working example, however, is a factor to be considered, especially in a case involving an unpredictable and undeveloped art.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure:
The prior art is undeveloped for the role that GPLD1 plays in improving cognitive function of any aged individual, and it is unpredictable that administering GPLD1 locally to the brain would provide improved cognitive function to any aged individual as broadly claimed. The specification does not provide sufficient guidance on using any variant of the GPLD1 of the instant application to improve cognitive function of any aged individual by administering locally to the brain.
Without further guidance, one of skill in the art would have to practice a substantial amount of trial-and-error experimentation, an amount considered undue and not routine, to practice the instantly 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 1-10, 13-19, 21, and 27-31 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.
Claims 1, 10, 19, 21 recite “a Gpld1 polypeptide comprising a region having at least 95% identity to amino acid sequence 24-840 of SEQ ID NO: 1”. The claim is unclear what ‘amino acid sequence 24-840’ is referring to, thus is indefinite. To obviate this rejection, Applicant may amend to “a Gpld1 polypeptide comprising a region having at least 95% identity to amino acid positions 24-840 according to SEQ ID NO: 1”. Claims 27 and 30 are also rejected for similar claim construction “…amino acid sequence 24-180 of SEQ ID NO:1”. Claims 2-9, 13-18, 28-29, and 31 are likewise rejected as being dependent on an indefinite 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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-5, 19, and 30 are rejected under 35 U.S.C. 103 as being obvious over Yanagi (JP 2004059550 A) in view of Ostergaard et al. (Journal of Cerebral Blood Flow & Metabolism 2016, Vol. 36(2) 302–325, hereinafter “Ostegaard”).
Yanagi teaches treating collagenosis or autoimmune diseases with a glycosylphosphatidylinositol anchor-type phospholipase D (GPI-PLB) or its gene (abstract). Yanagi teaches GPI-PLD present in plasma binds to a high-density lipoprotein (HDL) fraction in vivo and migrates in plasma, fragmented DNA from apoptotic cells and the DNA-binding protein are protected by the HDL bound to the GPI-PLD, thereby inhibiting exposure to immune cells, the fragmented DNA are then rapidly absorbed via the HDL receptor expressed on the cell membrane surface of phagocytic cells (macrophages) and the like (pg. 3, para 14). Yanagi teaches the GPI-PLD can be administered by intravenous injection, oral administration, intramuscular administration, intraperitoneal administration, subcutaneous administration and the like, to a human which meets the limitations in claims 1-5 (pg. 4, para 21). Yanagi teaches methods for purifying human GPI-PLD can be prepared using an affinity column and concentrated and has no toxicity when administered intravenously (pg. 4, para 17-18). Yanagi teaches the GPI-PLD protein may be encapsulated in an appropriate coat protein, liposome, virus particle, or the like, or the gene may be incorporated into an expression vector after administration so that the GPI-PLD is expressed in a target cell which meets the limitation in claim 19 (pg. 4, para 20 & 22).
Yanagi teaches the GPI-PLD (accession # ADM30834, SEQ ID NO: 2) has 99.7% sequence identity to amino acid positions 24-840 of instant SEQ ID NO:1 and 100% sequence identity to amino acid positions 24-180 of instant SEQ ID NO: 1, which meets the limitations in claims 1, 19, and 30 (See sequence comparison below).
Yanagi is silent regarding administering GPI-PLD to ameliorate age-related cognitive function. In other words, Yanagi teaches administering the GPI-PLD to an individual systemically, but does not teach that the method would improve cognitive decline.
However, Ostegaard teaches cerebral small vessel disease (SVD) gives rise to one in five strokes worldwide and constitutes a major source of cognitive decline in the elderly (abstract). Ostegaard teaches SVD is known to occur in relation to hypertension, diabetes, smoking, radiation therapy and in a range of inherited and genetic disorders, autoimmune disorders, connective tissue disorders (collagenosis), and infections, including Alzheimer’s disease (AD) (abstract, pg. 305, col. 1, para 4). Ostegaard teaches the apolipoprotein (APOE) ꜫ4 allele is associated with both CAA and the development of AD (Table 2) (pg. 306, col. 2, para 4). Ostegaard teaches attenuation of functional hyperemia can also be observed immediately after administration of angiotension II (AT2) and amyloid β (Aβ) in animal models of hypertension and AD/amyloidosis, respectively (Table 2) and antedates any morphological changes in the vessel wall or brain parenchyma and even the development of high blood pressure in the model of hypertension, which are consistent with capillary dysfunction caused by pericyte constrictions and compensatory increase in vascular smooth muscle cell (VSMC) tone to limit flow responses (pg. 309, col. 1, para 1).
Therefore, 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 utilize the method of administering GPI-PLD to an individual to treat collagenosis or autoimmune disease as taught by Yanagi, towards improving cognitive decline based on the teachings of Ostergaard, which links collagenosis or autoimmune disease with cognitive impairment. One of ordinary skill in the art would have been motivated to try Yanagi’s method of administering GPI-PLD to ameliorate age-related cognitive decline based on the knowledge that GPI-PLD binds to apolipoprotein A1 and the like in plasma taught by Yanagi [0008], which the apolipoprotein is associated with the development of AD as taught by Ostergaard.
Sequence comparison of ADM30834 and 24-840AA of instant SEQ ID NO: 1
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Claims 6-9 and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Yanagi in view of Ostergaard as applied to claims 1-5, 19, and 30 above, and further in view of Cai et al. (PNAS, 2006, vol. 103, no. 6, pgs. 1941-46, cited in PTO-892 mailed 12/24/2024, hereinafter “Cai”), Naslund et al. (JAMA, 2000, vol. 283, no. 12, pgs. 1571-1577, cited in PTO-892 mailed 12/24/2024, hereinafter “Naslund”) and D’Andrea (Medical Hypotheses (2005) 64, 458–463, cited in PTO-892 mailed 12/24/2024).
Yanagi teaches that decreased GPI-PLD activity may directly cause collagen diseases and autoimmune diseases, thus administering a wild-type or active GPI-PLD would be an effective therapeutic agent (pg. 3, para 15). Ostergaard teaches the relation of collagenosis, autoimmune diseases, and Alzheimer’s disease in the elderly and cognitive decline. D’Andrea teaches current reports suggest Alzheimer’s as an innate autoimmune disease (title, abstract). Yanagi’s method does not explicitly disclose the individual administered the GPI-PLD is at least 50 years old, nor has mild cognitive impairment, dementia, or Alzheimer’s disease.
However, Cai discloses GPI-PLD as a negative regulator of B-amyloid (Aβ) formation, the major contributor to Alzheimer’s disease (title). Cai teaches overexpression of wild-type GPI-PLD resulted in reduced AB generation, and conversely down-regulation of endogenous GPI-PLD by a small hairpin RNA elevates AB production (abstract). Cai suggests by modulating PLD1 expression levels may lead to the development of novel therapeutic approaches for delaying or preventing Alzheimer’s disease (pg. 1945, col. 1, para 1).
Likewise, Naslund teaches a correlation between elevated levels of AB in the brain and cognitive decline (title). Naslund teaches levels of AB were elevated in cases classified as having questionable dementia (CDR score = 0.5), and increases of both peptides correlated with progression of dementia which meets the limitation of claims 1, 7-9, and 31 (abstract). Naslund teaches the autopsied subjects analyzed in the study were all submitted to an ongoing nursing care resulting from cognitive impairment and/or, in the case of nondemented subjects, a physical condition such as incomplete recovery following a fracture, which meets the limitation of claims 7-8 (pg. 1572, sec. Subjects). The subjects were classified based on CDR scores, and had an average age range of 83-89 at time of death, which meets the limitation of claim 6 (pg. 1572, Table 1).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to utilize the method of administering GPI-PLD that has 95% identity to aa positions 24-840 according to instant SEQ ID NO: 1, for treating an autoimmune disease, such as Alzheimer’s, as taught by Yanagi and D’Andrea, thereby improving cognitive function based on the teachings of Ostergaard, which would reduce generation of AB formation in the brain as taught by Cai, thereby improving cognitive function in the individual due to the reduction in accumulated AB plaques in individuals over 50 years old, as taught by Naslund, with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to target activating GPI-PLD to increase its’ activity towards βAPP trafficking and inhibition of γ-secretase pathway, which is the activity that mediates proteolysis of β-amyloid precursor protein (βAPP) to generate β-amyloid (Aβ) as taught by Cai (pg. 1941, col. 1, para 1). Further, one of ordinary skill in the art would have been motivated to administer GPI-PLD to aged individual’s having at least one symptom of cognitive decline, which would indicate the probability of early onset dementia and/or Alzheimer’s disease due to accumulation of AB formation as taught by Naslund.
Claims 10, 21, 27, and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Yanagi in view of Ostergaard as applied to claims 1-5, 19, and 30 above, and further in view of Chakraborty et al. (US9089604B2, hereinafter “Chakraborty”).
Regarding claim 10, Yanagi teaches the GPI-PLD represented by SEQ ID NO: 2 can have one or several amino acids in the amino acid sequence that are deleted, substituted, or inserted (para 6). Yanagi does not explicitly teach the GPI-PLD administered has 100% identity to amino acid positions 24-840 according to instant SEQ ID NO: 1.
However, Chakraborty teaches a primary construct designed to encode one or more polypeptides of interest or fragments thereof, such as the polypeptide sequence according to SEQ ID NO: 48062, which has 100% identity to amino acid positions 24-840 according to instant SEQ ID NO: 1 (col. 17, lines 46-63, col. 41, line 62, see sequence comparison below).
Sequence comparison of AA positions 24-840 in SEQ ID NO: 48062 and instant SEQ ID NO: 1.
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Chakraborty teaches compositions, methods, processes, kits and devices for the design, preparation, manufacture and/or formulation of polynucleotides, primary constructs, and modified mRNA molecules (mmRNA) (col. 3, lines 63-68). Chakraborty teaches polynucleotides, primary constructs and mmRNA compositions and complexes in combination with one or more pharmaceutically acceptable excipients (col. 252, lines 55-58). Complexes, micelles, liposomes or particles can be prepared containing lipidoids and therefore, can result in an effective delivery of the polynucleotide, primary construct, or mmRNA, as judged by the production of an encoded protein, following the injection of a lipidoid formulation via localized and/or systemic routes of administration (col. 255, lines 37-43). Chakraborty teaches in one embodiment, a polynucleotide, primary construct, or mmRNA formulated with a lipidoid for systemic intravenous administration can target the liver col. 256, lines 12-14). Chakraborty teaches modified mRNAs and their encoded polypeptides may be used for treatment of any of a variety of disorders, such as Alzheimer’s disease (col. 313, lines 4-14). Chakraborty discloses Apo A-1 variant proteins have been shown to reduce susceptibility to Alzheimer’s disease, and have been associated with reduced cholesterol (col. 329, lines1-9). Yanagi also teaches GPI-PLD binds to apolipoprotein A1 and the like in plasma and is present in a high-density lipoprotein (HDL) fraction, which suggests an increase in GPI-PLD would likely increase apolipoprotein A1 to confer reduced susceptibility to Alzheimer’s disease (para 8).
Therefore 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 method for treating collagenosis or autoimmune disease taught by Yanagi thereby improving cognitive decline based on the teachings of Ostergaard linking collagenosis or autoimmune disease with cognitive impairment, by substituting the polypeptide administered to an individual according to SEQ ID NO: 48062 as taught by Chakraborty with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to administer SEQ ID NO: 48062, which has 100% identity to amino acid positions 24-840 according to instant SEQ ID NO: 1 because enhancing expression of systemic proteins, such as GPI-PLD which binds to apolipoprotein A1, would likely increase apolipoprotein A1 and confer reduced susceptibility to Alzheimer’s disease, thereby improving cognitive function in an individual, as taught by Chakraborty.
Regarding claims 21, 27, and 29, Yanagi teaches treating collagenosis or autoimmune diseases with a glycosylphosphatidylinositol anchor-type phospholipase D (GPI-PLB) or its gene (abstract). Yanagi teaches the GPI-PLD protein may be encapsulated in an appropriate coat protein, liposome, virus particle, or the like, or the gene may be incorporated into an expression vector after administration so that the GPI-PLD is expressed in a target cell which meets this limitation in claim 21 (pg. 4, para 20 & 22). Yanagi teaches the GPI-PLD (accession # ADM30834, SEQ ID NO: 2) has 99.7% sequence identity to amino acid positions 24-840 of instant SEQ ID NO:1 and 100% sequence identity to amino acid positions 24-180 of instant SEQ ID NO: 1, which meets these limitations in claims 21 and 27 (See sequence comparison above).
Although Yanagi is silent regarding administering GPI-PLD to ameliorate age-related cognitive function, Yanagi teaches all the elements of the claimed method of administering the GPI-PLD to an individual systemically, except that the method would improve cognitive decling. However, Ostegaard teaches cerebral small vessel disease (SVD) gives rise to one in five strokes worldwide and constitutes a major source of cognitive decline in the elderly (abstract). Ostegaard teaches SVD is known to occur in relation to hypertension, diabetes, smoking, radiation therapy and in a range of inherited and genetic disorders, autoimmune disorders, connective tissue disorders (collagenosis), and infections, including Alzheimer’s disease (AD) (abstract, pg. 305, col. 1, para 4). Ostegaard teaches the apolipoprotein (APOE) ꜫ4 allele is associated with both CAA and the development of AD (Table 2) (pg. 306, col. 2, para 4). Ostegaard teaches attenuation of functional hyperemia can also be observed immediately after administration of angiotension II (AT2) and amyloid β (Aβ) in animal models of hypertension and AD/amyloidosis, respectively (Table 2) and antedates any morphological changes in the vessel wall or brain parenchyma and even the development of high blood pressure in the model of hypertension, which are consistent with capillary dysfunction caused by pericyte constrictions and compensatory increase in vascular smooth muscle cell (VSMC) tone to limit flow responses (pg. 309, col. 1, para 1).
Yanagi does not explicitly teach the expression construct is introduced to a hepatocyte derived from the individual and modified ex vivo, then introduced back into the individual as recited in claim 21. Yanagi also does not explicitly teach the nucleic acid construct is introduced into the liver.
However, Chakraborty teaches the primary construct that can comprise a GPI-PLD construct or nucleic acid encoding said construct, can be transfected ex vivo into cells, which are subsequently transplanted into a subject (col. 279, lines 24-26). Chakraborty teaches the invention provides for the repeated introduction (e.g. transfection) of modified nucleic acids into a target cell population, e.g., in vitro, ex vivo, in situ, or in vivo, and achievable in a diverse array of cell types and within a variety of tissues, such as the hepatocytes cell line HepG2 (col. 331, lines 10-23, col. 332, line 21). Chakraborty also teaches formulations comprising the nucleic acid encoding the primary construct may also be constructed or compositions altered such that they passively or actively are directed to different cell types in vivo, including but not limited to hepatocytes (i.e. the liver) (col. 266, lines 3-18).
Therefore, 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 utilize the method of administering GPI-PLD to an individual to treat collagenosis or autoimmune disease by introducing a genetically modifying construct into hepatocytes of an individual ex vivo as taught by Yanagi, thereby improving cognitive decline based on the teachings of Ostergaard linking collagenosis or autoimmune disease with cognitive impairment, and then introducing those genetically modified hepatocytes back into the individual as taught by Chakraborty with a reasonable expectation of success. It also would have been prima facie obvious to introduce a nucleic acid construct encoding the GPI-PLD taught by Yanagi, and introduce said construct into the liver as taught by Chakraborty with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to modify the methods taught by Yanagi to specifically enhance GPI-PLD levels systemically by using routine and well understood laboratory techniques of introduction as taught by Chakraborty.
Claims 13-18 are rejected under 35 U.S.C. 103 as being unpatentable over Yanagi in view of Ostergaard as applied to claims 1-5, 19, and 30 above, and further in view of Cai, Naslund, and Jacobsen et al. (JP2012233002A, cited in PTO-892 mailed 12/27/2024, hereinafter “Jacobsen”).
Regarding claims 13 and 14, Yanagi does not teach the GPI-PLD’s association with cognitive functioning, however Ostergaard teaches the link between collagenosis and autoimmune disease and they’re effect on cognitive decline in the elderly. As discussed in the above 103 rejection, Cai and Naslund teach the link between GPI-PLD levels and the formation of AB plaques in Alzheimer’s patients and individuals over the age of 50. Yanagi does not explicitly teach the GPI-PLD is administered more than once as part of a treatment, or in an effective amount of 1ug to 1000ug per kg body weight of the individual.
However, Jacobsen teaches a method similar to the claimed method, by administering an amyloid beta antibody for improving cognition (title). Jacobsen teaches an ‘effective dose’ of the antibody administered can be in the range of 1 ug / kg body weight to 500 mg / kg body weight of the patient, which encompasses the claimed range in claim 13 (pg. 7, para 4). In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) Jacobsen also teaches subjects can be administered doses daily, every other day, once a week, or according to any other schedule determined by empirical analysis (pg. 35, para 9).
Therefore it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to administer the GPI-PLD/GPLD1 polypeptide to an individual to treat collagenosis or autoimmune disease taught by Yanagi, for reducing AB plaques in Alzheimer patients and individuals over the age of 50 as disclosed by Cai and Naslund, and incorporate the dosage and treatment regimen taught by Jacobsen, thereby improving cognitive decline based on the teachings of Ostergaard linking collagenosis or autoimmune disease with cognitive impairment. One of ordinary skill in the art would have been motivated to tailor the dosage and treatment regimen based on the individual and empirical evidence of improved cognitive function when reducing AB plaques as taught by Jacobsen.
Regarding claims 15-18, Yanagi does not teach the GPI-PLD’s association with cognitive functioning, however Ostergaard teaches the link between collagenosis and autoimmune disease and they’re effect on cognitive decline in the elderly. As discussed above in the 103 rejection, Cai and Naslund teach the link between increased GPI-PLD levels reducing AB plaques seen in Alzheimer’s patients. Yanagi does not explicitly teach the course of treatment includes testing cognitive function as recited in the claims.
However, Jacobsen teaches a method similar to the claimed invention, by selecting patients with early to mid-stage Alzheimer's disease defined using the criteria of the Related Disorders Association (ADRDA), that score in the range of 12-26 on the Mini Mental State Exam (MMSE) or on a classical psychometric scale such as ADAS, will be assessed as a basal measurement before treatment which meets the limitation of claim 15 (pg. 38, para 5). These psychometric scales provide a measure of the progression of the Alzheimer's disease states and a suitable qualitative life scale can also be used to monitor treatment (pg. 38, para 5). Jacobsen teaches after the basal measurement, the patient begins to receive treatment and are randomized and treated with either therapeutic agent or placebo in a blinded fashion (pg. 38, para 6). Patients are monitored at least every 6 months and efficacy is measured by a significant reduction in treatment group progression relative to the placebo group which meets the limitation of claim 16 (pg. 38, para 6). Jacobsen teaches mice administered with the antibodies are assessed for improvement in cognition (i.e. contextual and clue-dependent memory) which meets the limitation of claim 17 (pg. 43, para 6). Jacobsen teaches several tests have been developed to assess cognitive skills, such as the Cambridge Neuropsychology Automated Examination, which assesses memory, attention and execution functions, which meets the limitations of claim 18 (pg. 34, para 11).
Therefore it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to administer the GPI-PLD/GPLD1 polypeptide to an individual to treat collagenosis or autoimmune disease taught by Yanagi, for reducing AB plaques in Alzheimer patients and individuals over the age of 50 as disclosed by Cai and Naslund, thereby improving cognitive decline based on the teachings of Ostergaard linking collagenosis or autoimmune disease with cognitive impairment, and incorporate assessment of improved cognitive function during the course of treatment by assessing memory and executive functions with the psychometric tests taught by Jacobsen with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to incorporate these cognition tests to determine treatment of the individual was effective.
Claim 28 is rejected under 35 U.S.C. 103 as being unpatentable over Yanagi in view of Ostergaard and Chakraborty as applied to claims 10, 21, and 27 above, and further in view of Cai, Naslund, and D’Andrea.
As discussed above, Yanagi teaches that decreased GPI-PLD activity may directly cause collagen diseases and autoimmune diseases, thus administering a wild-type or active GPI-PLD would be an effective therapeutic agent (pg. 3, para 15). Ostergaard teaches the link between collagenosis and autoimmune disease and they’re effect on cognitive decline in the elderly. D’Andrea discloses current reports suggest Alzheimer’s as an innate autoimmune disease (title, abstract). Chakraborty teaches the primary construct that can comprise a GPI-PLD construct or nucleic acid encoding said construct, can be transfected ex vivo into cells, which are subsequently transplanted into a subject. Neither Yanagi nor Chakraborty explicitly teach the individual administered the genetically modified hepatocytes expressing the GPI-PLD, has mild cognitive impairment, dementia, or Alzheimer’s disease.
However, Cai discloses GPI-PLD as a negative regulator of B-amyloid (Aβ) formation, the major contributor to Alzheimer’s disease (title). Cai teaches overexpression of wild-type GPI-PLD resulted in reduced AB generation, and conversely down-regulation of endogenous GPI-PLD by a small hairpin RNA elevates AB production (abstract). Cai suggests by modulating PLD1 expression levels may lead to the development of novel therapeutic approaches for delaying or preventing Alzheimer’s disease (pg. 1945, col. 1, para 1).
Likewise, Naslund teaches a correlation between elevated levels of AB in the brain and cognitive decline (title). Naslund teaches levels of AB were elevated in cases classified as having questionable dementia (CDR score = 0.5), and increases of both peptides correlated with progression of dementia (abstract). Naslund teaches the autopsied subjects analyzed in the study were all submitted to an ongoing nursing care resulting from cognitive impairment and/or, in the case of nondemented subjects, a physical condition such as incomplete recovery following a fracture (pg. 1572, sec. Subjects).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to utilize the method of administering a GPI-PLD that has 95% identity to aa positions 24-840 according to instant SEQ ID NO: 1 by introducing enhance expression of the GPI-PLD by genetically modified hepatocytes, as taught by Yanagi and Chakraborty, to treat an autoimmune disease, such as Alzheimer’s, which would reduce generation of AB formation in the brain in an individual due to the reduction in accumulated AB plaques in individuals with Alzheimer’s disease, as taught by Cai and Naslund, thereby improving cognitive decline based on the teachings of Ostergaard linking collagenosis or autoimmune disease with cognitive impairment. One of ordinary skill in the art would have been motivated to enhance activating GPI-PLD which would increase its’ activity towards βAPP trafficking and inhibition of γ-secretase pathway, which is the activity that mediates proteolysis of β-amyloid precursor protein (βAPP) to generate β-amyloid (Aβ) as taught by Cai (pg. 1941, col. 1, para 1). Further, one of ordinary skill in the art would have been motivated to administer GPI-PLD to aged individual’s having at least one symptom of cognitive decline, which would indicate the probability of early onset dementia and/or Alzheimer’s disease due to accumulation of AB formation as taught by Naslund.
Response to Arguments
Applicant’s arguments, see pages 5-8, filed June 27, 2025, with respect to the rejection(s) of claim(s) 1-10, 13-19, 21, and 27-31 under 112(a) lack of enablement have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made under 112(a) scope of enablement due to Applicant’s amendment to the claims and remarks. As described above, the role of Gpld1 in improving cognitive function when administered locally to the brain to any aged individual is lacking in the prior art, and the working examples fail to show this as well.
Applicant's arguments filed June 27, 2025 have been fully considered but they are not persuasive.
Regarding remarks directed to the previous 103 rejection, Applicant argues Yanagi does not recite the GPI-PLD1 will improve cognitive function. Applicant also argues D'Andrea does not establish Alzheimer's disease is an autoimmune disease but is more probable that the cause of AD is the result of a myriad of intertwining pathologies. Applicant argues Cai does not teach Gpld1, but a different protein Pld1, thus the combined teachings of these references do not result in the claimed invention. Applicant argues similarly for the 103 rejection of Yanagi in view of Masuda, and Yanagi in view of Schofield. (remarks, pgs. 8-11).
As an initial matter, the new amendments to claims 1, 19, and 21 filed 6/27/2025 now recite improving cognitive function in an individual by administering the GPI-PLD systemically or locally to the brain, thereby improving cognitive function. Yanagi teaches all the claimed method elements, but is silent as to the improvement of cognitive function, however, Ostergaard teaches the link between collagenosis, autoimmune disease, and Alzheimer’s and their effect on cognitive decline in the elderly, as discussed in the 103 rejection.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Yanagi teaches a method of administering the claimed GPI-PLD for treating autoimmune diseases, wherein D'Andrea suggests Alzheimer's as an innate autoimmune disease, and Ostergaard teaches the link between collagenosis, autoimmune disease, and Alzheimer’s disease and their effect on cognitive decline. Cai teaches GPI-PLD’s role in negatively regulating AB production, which eleveated AB levels are widely seen in patients with Alzheimer’s disease, as taught by Naslund. Thus it would be prima facie obvious to combine the cited references to arrive at the claimed invention.
Conclusion
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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/JESSICA EDWARDS/
Examiner, Art Unit 1657