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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 12/22/25 has been entered.
Claim 45 has been added by Applicant.
Claims 2, 4, 5, 7-13, 35, 37, 43-45 are pending.
Claims 2, 7-9, 43, and 44 have been amended by Applicant.
Claims 2, 4, 5, 7-13, 35, 37, 43-45 are currently under consideration.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This Office Action contains New Rejections.
Rejections Withdrawn
All previous rejections are withdrawn.
New Rejections
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2, 4, 5, 7-13, 35, 37, 43-45 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 2 recites “A method for treating dysregulated lipid metabolism…wherein cells expressing TREM2 in the mammal exhibit dysregulated lipid metabolism…wherein the dysregulated metabolism comprises….” It is unclear whether “the dysregulated lipid metabolism” is the dysregulated lipid metabolism that the method is for treating and/or the dysregulated lipid metabolism exhibited by cells expressing TREM2. There is insufficient antecedent basis for “the dysregulated lipid metabolism” in the claims.
Claim Rejections - 35 USC § 103
Claim(s) 2, 4, 5, 7-10, 12, 35, 37, 43, and 45 is/are rejected under 35 U.S.C. 103 as being unpatentable over Schwabe et al (WO 2017/062672 A2; 4/13/17; 11/6/24 IDS) in view of Wong et al (Alzheimer’s & Dementia, 1027, 810-827), Gong et al (Journal of Histochemistry & Cytochemistry, 2013, 6(12): 857-868), Guerreiro et al (NEJM, 2013, 368(2): 117-127), Cantoni et al (Acta Neuropathol, 2015, 129: 429-447), and Kersten (Biochimica et Biophysica, 2014, 1841: 919-933).
Schwab et al teaches TREM2 is expressed on myeloid cells ([0004], in particular). Schwabe et al teaches a method of treating Alzheimer’s disease (AD) in a mammal subject comprising administering to the mammal subject an effective amount of agonist anti-TREM2 antibody 7E5 (see Example 16, Fig. 8A, and Fig. 9A, in particular). Example 16 of Schwabe et al teaches, in mouse models of AD, anti-TREM2 antibody 7E5 has been shown to: (i) modulate inflammatory signaling by decreasing level of CD11c and increasing levels of Fabp3, CCL2, CXCL10, Rorc, Fab5, and TNFa; (ii) improve special learning and memory defects; and (iii) improve cognitive learning. Schwabe et al further teachers 7E5 induces pro-inflammatory signals (Example 13, in particular).
Schwabe et al does not specifically teach the mammal subject with AD has dysregulated lipid metabolism and/or increased accumulation of one or more lipids, such as triacylglycerides or cholesterol esters. However, these deficiencies are made up in the teachings of Wong et al, Gong et al, Guerreiro et al, Cantoni et al, Kersten.
At the right column on page 811, Wong et al teaches: “There is a strong body of evidence from both animal models and studies in humans that associate abnormal lipid metabolism with AD (Fig. 1). The main classes known to be disrupted in AD include cholesterol, sphingolipids, phospholipids, and glycerolipids including gangliosides.” Wong further teaches a 40% reduction in sulfatide (recited by instant claim 7) correlating with clinical dementia and a sulfatide/PI ratio correlating with incident AD (Table 1, in particular). Wong further teaches the ganglioside (recited by instant claim 11) GAb as a being found in human brain during AD and suggests GAb as an important biomarker for early detection of AD pathology (page 814, in particular).
Gong et al teaches lipoprotein lipase (LPL) is known to be responsible for hydrolyzing lipids (left column on page 858, in particular) and exhibits markedly reduced levels in the dentate gyrus of AD brains (Abstract, in particular).
Guerreiro et al teaches the presence of T66M TREM2 loss-of-function variants in patients with AD (right column on page 120, in particular).
Cantoni et al teaches loss of TREM2 results in microglia (a type of myeloid cell) with defects in lipid metabolism, a decrease in lipoprotein lipase (LPL), and defective myelin (which is known in the prior art as a lipid sheath) degradation (page 441, in particular).
The Abstract of Kersten teaches LPL, which is taught by Cantoni et al to be decreased in microglia with reduced TREM2, hydrolyzes triacylglyceride (same as “triglyceride”). Using a mouse model overexpressing LPL, Kersten further teaches elevated expression of LPL results in reduction in triacylglyceride (right column on page 919, in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, perform the method of Schwabe et al to treat the just any subject with AD by administering an agonist anti-TREM2 antibody because the method of Schwabe et al is taught to provide therapeutic benefit to subjects with AD by administering an agonist of TREM2. Such subjects include: subjects with AD having just any cells exhibiting abnormal lipid metabolism described by Wong et al and/or accumulation of just any lipid; subjects with abnormal deposits of cholesterol esters described by Lobanova et al; mammalian subjects with reduced TREM2 activity, such as a subject with AD found to have a T66M TREM2 loss-of-function mutation taught by Guerreiro et al exhibits reduced TREM2 activity, that would predictably result in the subject having microglia with defects in lipid metabolism because Cantoni et al teaches loss of TREM2 results in microglia with defects in lipid metabolism, defects in myelin degradation, and reduction in LPL - which would predictably result in accumulation of lipids such as triacylglyceride due to loss of LPL hydrolysis of triacylglyceride because Kersten teaches LPL hydrolyzes triglycerides and Kersten teaches (in a transgenic mouse model) expression level of LPL (which hydrolyzes triacylglyceride) inversely correlating with levels of triacylglyceride (right column on page 919, in particular); and just any subject with AD “prone to” any other recited condition.
Reduction in lipid accumulation would predictably occur when performing the combined method with an AD subject found to have reduced TREM2 activity because the administered TREM2 agonist would predictably reverse lipid accumulation due to low TREM2 activity. Further, while the cited references do not demonstrate the combined method results in reduced expression of pro-inflammatory cytokines recited by instant claim 12, the method appears to be the same absent a showing otherwise.
Further, the examiner takes the positions that reduction of expression of pro-inflammatory cytokines recited by instant claim 12 is not a property having significance greater than that of the expected property of a predicted therapeutic effect of treating AD taught by the cited references. Therefore, recitation that the combined method has the property of being able to reduce expression of pro-inflammatory cytokines recited by instant claim 12 is not sufficient to rebut obviousness of the combined method when combined method is expected to have the equal or greater property of expected therapeutic benefit. See MPEP 716.02(c). Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results. Further, see In re Baxter Travenol Labs., 952 F.2d 388, 21 USPQ2d 1281 (Fed. Cir. 1991), where the court held that the fact that another advantage would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Response to Arguments
In the Reply of 12/22/25, Applicant argues neither Cantoni nor Kersten teach directly evaluating lipid levels, provide data showing LPL activity, show increase accumulation of cholesteryl esters or tracylglycerides, show correction of accumulated cholesteryl esters or triacylglycerides using an agonist anti-TREM-2 antibody, or show any data supporting an impact on LPL activity or an accumulation of cholesteryl ester/triacylglyceride as a result of reduced LPL expression levels. Applicant further argues the examiner has failed to establish that one skilled in the art reviewing cited documents would have had the motivation to practice the claimed method. Applicant further argues the examiner has failed to establish that one skilled in the art reviewing cited documents would have had a reasonable expectation that reduced LPL expression observed by Cantoni et al would have resulted in cholesteryl ester/triacylglyceride accumulation. Applicant further argues the examiner has failed to establish that one skilled in the art reviewing cited documents would have had a reasonable expectation that admission of an agonist of anti-TREM2 antibody would have treated cholesteryl ester/triacylglyceride accumulation.
The amendments to the claims and the arguments found in the Reply of 12/22/25 have been carefully considered, but are not deemed persuasive. In regards to the arguments that neither Cantoni nor Kersten teach directly evaluating lipid levels, provide data showing LPL activity, show increase accumulation of cholesteryl esters or tracylglycerides, show correction of accumulated cholesteryl esters or triacylglycerides using an agonist anti-TREM-2 antibody, or show any data supporting an impact on LPL activity or an accumulation of cholesteryl ester/triacylglyceride as a result of reduced LPL expression levels, Applicant is arguing limitations not recited by the claims. The claims do not recite directly evaluating lipid levels. The claims do not recite providing data showing LPL activity. The claims do not recite showing an increase in accumulation of cholesteryl esters or tracylglycerides. The claims do not recite correcting accumulated cholesteryl esters or triacylglycerides using an agonist anti-TREM-2 antibody. The claims do not recite showing data supporting an impact on LPL activity or an accumulation of cholesteryl ester/triacylglyceride as a result of reduced LPL expression levels. The rejection is based on performing the method of Schwabe et al to treat the just any subject with AD by administering an agonist anti-TREM2 antibody to the subject because the method of Schwabe et al is taught to provide therapeutic benefit to subjects with AD by administering an agonist of TREM2. Such subjects predictably include mammalian subjects with reduced TREM2 activity, such as a subject with AD found to have a T66M TREM2 loss-of-function mutation taught by Guerreiro et al exhibits reduced TREM2 activity, that would predictably result in the subject having microglia with defects in lipid metabolism because Cantoni et al teaches loss of TREM2 results in microglia with defects in lipid metabolism, defects in myelin degradation, and reduction in LPL - which would predictably result in accumulation of lipids such as triacylglyceride due to loss of LPL hydrolysis of triacylglyceride because Kersten teaches LPL hydrolyzes triglycerides and Kersten teaches (in a transgenic mouse model) expression level of LPL (which hydrolyzes triacylglyceride) inversely correlating with levels of triacylglyceride (right column on page 919, in particular). Reduction in lipid accumulation would predictably occur when performing the combined method with an AD subject found to have reduced TREM2 activity because the administered TREM2 agonist would predictably reverse lipid accumulation due to low TREM2 activity.
In regards to the argument the examiner has failed to establish that one skilled in the art reviewing cited documents would have had the motivation to practice the claimed method, the examiner disagrees. As stated above, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, perform the method of Schwabe et al to treat the just any subject with AD by administering an agonist anti-TREM2 antibody because the method of Schwabe et al is taught to provide therapeutic benefit to subjects with AD by administering an agonist of TREM2. Such AD subjects include those with recited dysregulated lipid metabolism for the reasons stated above.
In regards to the argument the examiner has failed to establish that one skilled in the art reviewing cited documents would have had a reasonable expectation that reduced LPL expression observed by Cantoni et al would have resulted in cholesteryl ester/triacylglyceride accumulation, the examiner disagrees. One would have reasonably predicted reduced LPL results in elevated levels of triacylglyceride because Kersten teaches (in a transgenic mouse model) expression level of LPL (which hydrolyzes triacylglyceride) inversely correlates with levels of triacylglyceride (right column on page 919, in particular). The rejection is based on reasonable expectation of success, not “absolute” predictability. See MPEP 2143.02.
In regards to the argument that the examiner has failed to establish that one skilled in the art reviewing cited documents would have had a reasonable expectation that admission of an agonist of anti-TREM2 antibody would have treated cholesteryl ester/triacylglyceride accumulation, “treating dysregulated lipid metabolism in a mammal in need thereof” encompasses methods of administering a therapeutic treatment to a mammal with AD that happens to have recited dysregulated lipid metabolism. Such a method is rendered obvious for the reasons stated above. However, reduction in lipid accumulation would predictably occur when performing the combined method with an AD subject found to have a T66M TREM2 loss-of-function mutation taught by Guerreiro et al to be indicative of reduced TREM2 activity because the administered TREM2 agonist would predictably reverse lipid accumulation due to low TREM2 activity.
Claim Rejections - 35 USC § 103
Claim(s) 2, 4, 5, 7-10, 12, 13, 35, 37, 43, and 45 is/are rejected under 35 U.S.C. 103 as being unpatentable over Schwabe et al (WO 2017/062672 A2; 4/13/17; 11/6/24 IDS) in view of Wong et al (Alzheimer’s & Dementia, 1027, 810-827), Gong et al (Journal of Histochemistry & Cytochemistry, 2013, 6(12): 857-868), Guerreiro et al (NEJM, 2013, 368(2): 117-127), Cantoni et al (Acta Neuropathol, 2015, 129: 429-447), and Kersten (Biochimica et Biophysica, 2014, 1841: 919-933) as applied to claims 2, 4, 5, 7-10, 12, 35, 37, 43, and 45 above, and further in view of Crunkhorn (Nature Reviews Drug Discovery, 2012, 11(271)).
Teachings of Schwabe et al, Wong et al, Gong et al, Guerreiro et al, Cantoni et al, and Kersten are discussed above.
Schwabe et al, Wong et al, Gong et al, Guerreiro et al, Cantoni et al, and Kersten do not teach administering an RXR agonist. However, these deficiencies are made up in the teachings of Crunkhorn.
Crunkhorn teaches administering an RXR agonist reverses AD (see title and entire article, in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of treating AD of Schwabe et al, Wong et al, Gong et al, Guerreiro et al, Cantoni et al, and Kersten wherein the subject with AD is further administered an RXR agonist in an effort to obtain further therapeutic benefit for the subject with AD because Crunkhorn teaches administering an RXR agonist reverses AD. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Claim Rejections - 35 USC § 103
Claim(s) 2, 4, 5, 7-10, 12, 35, 37, and 43-45 is/are rejected under 35 U.S.C. 103 as being unpatentable over Schwabe et al (WO 2017/062672 A2; 4/13/17; 11/6/24 IDS) in view of Wong et al (Alzheimer’s & Dementia, 1027, 810-827), Gong et al (Journal of Histochemistry & Cytochemistry, 2013, 6(12): 857-868), Guerreiro et al (NEJM, 2013, 368(2): 117-127), Cantoni et al (Acta Neuropathol, 2015, 129: 429-447), and Kersten (Biochimica et Biophysica, 2014, 1841: 919-933) as applied to claims 2, 4, 5, 7-10, 12, 35, 37, 43, and 45 above, and further in view of Saher et al (Biochimica et Biophysica Acta, 2015, 1851: 1083-1094).
Teachings of Schwabe et al, Wong et al, Gong et al, Guerreiro et al, Cantoni et al, and Kersten are discussed above.
Schwabe et al, Wong et al, Gong et al, Guerreiro et al, Cantoni et al, and Kersten do not specifically teach the accumulated lipids of the microglia of the combined method include free cholesterol. However, these deficiencies are made up in the teachings of Saher et al.
Saher et al teaches the largest pool of free cholesterol in mammals resides in myelin membranes (Abstract, in particular), which are taught by Cantoni et al to exhibit defective degradation with reduced TREM2.
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of treating AD of Schwabe et al, Wong et al, Gong et al, Guerreiro et al, Cantoni et al, and Kersten wherein the lipid accumulation due to microglia cells of the combined method exhibiting TREM2 loss or deficiency includes free cholesterol because Cantoni et al teaches reduced TREM2 results in defective degradation of myelin membranes – the location of the largest pool of free cholesterol in mammals. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Claim Rejections - 35 USC § 103
Claim(s) 2, 4, 5, 7-10, 12, 35, 37, 43, and 45 is/are rejected under 35 U.S.C. 103 as being unpatentable over Schwabe et al (WO 2017/062672 A2; 4/13/17; 11/6/24 IDS) in view of Wong et al (Alzheimer’s & Dementia, 1027, 810-827), Lobanova et al (arXiv, 2018, 1803.01201, 11 pages), Gong et al (Journal of Histochemistry & Cytochemistry, 2013, 6(12): 857-868), Guerreiro et al (NEJM, 2013, 368(2): 117-127), Cantoni et al (Acta Neuropathol, 2015, 129: 429-447), and Kersten (Biochimica et Biophysica, 2014, 1841: 919-933).
Schwab et al teaches TREM is expressed on myeloid cells ([0004], in particular). Schwabe et al teaches a method of treating Alzheimer’s disease (AD) in a mammal subject comprising administering to the mammal subject an effective amount of agonist anti-TREM2 antibody 7E5 (see Example 16, Fig. 8A, and Fig. 9A, in particular). Example 16 of Schwabe et al teaches, in mouse models of AD, anti-TREM2 antibody 7E5 has been shown to: (i) modulate inflammatory signaling by decreasing level of CD11c and increasing levels of Fabp3, CCL2, CXCL10, Rorc, Fab5, and TNFa; (ii) improve special learning and memory defects; and (iii) improve cognitive learning. Schwabe et al further teachers 7E5 induces pro-inflammatory signals (Example 13, in particular).
Schwabe et al does not specifically teach the mammal subject with AD has dysregulated lipid metabolism and/or increased accumulation of one or more lipids, such as triacylglycerides or cholesterol esters. However, these deficiencies are made up in the teachings of Wong et al, Lobanova et al, Gong et al, Guerreiro et al, Cantoni et al, Kersten.
At the right column on page 811, Wong et al teaches: “There is a strong body of evidence from both animal models and studies in humans that associate abnormal lipid metabolism with AD (Fig. 1). The main classes known to be disrupted in AD include cholesterol, sphingolipids, phospholipids, and glycerolipids including gangliosides.” Wong further teaches a 40% reduction in sulfatide (recited by instant claim 7) correlating with clinical dementia and a sulfatide/PI ratio correlating with incident AD (Table 1, in particular). Wong further teaches the ganglioside (recited by instant claim 11) GAb as a being found in human brain during AD and suggests GAb as an important biomarker for early detection of AD pathology (page 814, in particular).
Lobanova et al teaches abnormal deposits of cholesterol esters in amyloid-b plaques of AD human brains (Abstract, in particular).
Gong et al teaches lipoprotein lipase (LPL) is known to be responsible for hydrolyzing lipids (left column on page 858, in particular) and exhibits markedly reduced levels in the dentate gyrus of AD brains (Abstract, in particular).
Guerreiro et al teaches the presence of T66M TREM2 loss-of-function variants in patients with AD (right column on page 120, in particular).
Cantoni et al teaches loss of TREM2 results in microglia with defects in lipid metabolism, a decrease in lipoprotein lipase (LPL), and defective myelin (which is known in the prior art as a lipid sheath) degradation (page 441, in particular).
The Abstract of Kersten teaches LPL, which is taught by Cantoni et al to be decreased in microglia with reduced TREM2, hydrolyzes triacylglyceride (same as “triglyceride”). Using a mouse model overexpressing LPL, Kersten further teaches elevated expression of LPL results in reduction in triacylglyceride (right column on page 919, in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, perform the method of Schwabe et al to treat the just any subject with AD by administering an agonist anti-TREM2 antibody because the method of Schwabe et al is taught to provide therapeutic benefit to subjects with AD by administering an agonist of TREM2. Such subjects include: subjects with AD having just any cells exhibiting abnormal lipid metabolism described by Wong et al and/or accumulation of just any lipid; subjects with abnormal deposits of cholesterol esters described by Lobanova et al; mammalian subjects with reduced TREM2 activity, such as a subject with AD found to have a T66M TREM2 loss-of-function mutation taught by Guerreiro et al exhibits reduced TREM2 activity, that would predictably result in the subject having microglia with defects in lipid metabolism because Cantoni et al teaches loss of TREM2 results in microglia with defects in lipid metabolism, defects in myelin degradation, and reduction in LPL - which would predictably result in accumulation of lipids such as triacylglyceride due to loss of LPL hydrolysis of triacylglyceride because Kersten teaches LPL hydrolyzes triglycerides and Kersten teaches (in a transgenic mouse model) expression level of LPL (which hydrolyzes triacylglyceride) inversely correlating with levels of triacylglyceride (right column on page 919, in particular); and just any subject with AD “prone to” any other recited condition.
Reduction in lipid accumulation would predictably occur when performing the combined method with AD subject found to have reduced TREM2 activity because the administered TREM2 agonist would predictably reverse lipid accumulation due to low TREM2 activity. Further, while the cited references do not demonstrate the combined method results in reduced expression of pro-inflammatory cytokines recited by instant claim 12, the method appears to be the same absent a showing otherwise.
Further, the examiner takes the positions that reduction of expression of pro-inflammatory cytokines recited by instant claim 12 is not a property having significance greater than that of the expected property of a predicted therapeutic effect of treating AD taught by the cited references. Therefore, recitation that the combined method has the property of being able to reduce expression of pro-inflammatory cytokines recited by instant claim 12 is not sufficient to rebut obviousness of the combined method when combined method is expected to have the equal or greater property of expected therapeutic benefit. See MPEP 716.02(c). Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results. Further, see In re Baxter Travenol Labs., 952 F.2d 388, 21 USPQ2d 1281 (Fed. Cir. 1991), where the court held that the fact that another advantage would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Conclusion
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/SEAN E AEDER/ Primary Examiner, Art Unit 1642