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 .
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The 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 122, 126-135, 136 & 140-141 are rejected under 35 U.S.C. 103 as being unpatentable over Lee et al (Neuron 2018) and Kang (US 2010/0299767)
Lee teaches a method of treating a subject diagnosed as having a neurocognitive disorder (NCD) by administering to the subject a transgene encoding one or more triggering receptor expressed on myeloid cells two (TREM2)
proteins (abstract). Lee developed BAC transgenic mice expressing human TREM2 (BAC-TREM2) in microglia. Lee found that elevated TREM2 expression reduced amyloid burden in the 5xFAD mouse model and that elevated TREM2 gene dosage led to improved memory performance in AD models {col 1 para 3). Lee engineered and created a BAC-TREM2-GFP reporter mouse line, which used the |same TREM2 BAC as BAC-TREM2 but express TREM2 protein with a C-terminal GFP fusion.
Lee further teaches that the NCD is a major NCD that interferes with the subject's behavior associated with memory, i.e. normal daily functioning (pg 1042, col 1, para 2, col 2, para 1 "To evaluate whether the neuroprotective phenotypes observed
in 5xFAD/TREM2 mice may correspond to a behavioral improvement, we performed the contextual fear-conditioning test, a hippocampus- dependent memory task that is compromised in 5xFAD mice ... Impressively, unlike the 5xFAD mice that exhibited a robust deficit in this task, the performance of 5xFAD/TREM2 mice is comparable to that of WT controls (Figure 7F). ... we conclude that the BAC-TREM2 transgene is improving both the neuritic pathology and cognitive performance in an amyloid mouse model of AD"). Since Lee teaches that behavioral deficits are ameliorated by overexpressing TREM2 in a mouse model, including a hippocampus-dependent memory task, it
would have been obvious to an artisan of ordinary skill in the art to experiment with using TREM2 overexpression to treat human major NCD, such as the memory deficit in Alzheimer's disease.Lee and Kang teach a method of treating a-subject diagnosed as having a neurocognitive disorder (NCD) the method including administering to the subject a transgene encoding TREM2 operatively linked to a high expression constitutive promoter. Lee further teaches that the NCD could be a mild NCD that is early in disease progression, and thus does not interfere with the subject's normal daily functioning (pg 1045, col 1, para 2 “Our study showed that BAC-TREM2 mice have elevated TREM2 levels as early as 2 months of age ... Thus, we favor a testable model that upregulation of TREM2 levels early in the AD mouse brains, prior to the upregulation of hundreds of other reactive microglial genes, may be more effective in reprogramming the microglial responsivity to ameliorate the disease.").
Lee does not expressly teach a population of cells containing TREM2 operably linked to a high expression constitutive promoter, however, it would have been obvious at the time the invention was field to use such a promoter because Kang teaches transforming cultured cells (and cells in animals) with TREM2 to overexpress the gene (para [0070] "The recombinant expression vector pcDNA3.1/TREM-2 was incorporated to colon cancer cells ... to overexpress TREM-2 gene", para (0023) "a transgenic animal which is transformed with TREM-2 gene to overexpress it", para [0052] "TREM-2 gene may be inserted to a chromosome of an animal according to any conventional transformation methods well known in the art. Kang teaches the use of a retroviral vector, or the like.", note, the vector pcDNA3.1 is commonly used in the art to express mammalian genes in mammalian cells, and comprises a constitutive, high level expression promoter from CMV (see Fig. 1)). Therefore it would have been obvious to an artisan of ordinary skill in the art to use any known method with various methods of creating transgenic expression of TREM2 to treat subjects having a neurocognitive disorder (NCD), including vectors that target a specific population of cells, such as the microglial cells of Lee, using a vector operably linked to a high expression constitutive promoter, such as the CMV promoter of Kang used to drive TREM2 expression.
Applicant is directed to pages 12-13 of KSR v Teleflex (500 US 398 2007) “ … the Court has held that a “patent for a combination which only unites old elements with no change intheir respective functions . . . obviously withdraws what is already known into the field of its monopoly and diminishes the resources available to skillful men.” Great Atlantic & Pacific Tea Co. v. Supermarket Equipment Corp., 340 U. S. 147, 152 (1950). This is a principal reason for declining to allow patents for what is obvious. The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” “When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one(emphasis added). If a person of ordinary skill can implement a predictable variation, §103 likely bars its patentability. For the same reason, if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond his or her skill.”
"[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); >see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.");< ** In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997).
Accordingly, the claimed invention was prima facie obvious to one of ordinary
skill in the art at the time the invention was made especially in the absence of evidence
to the contrary.
Claims 122-141 are rejected under 35 U.S.C. 103 as being unpatentable over Lee et al (Neuron 2018) and Kang (US 2010/0299767) & Bluebird (US 2017/0051308).
Lee teaches a method of treating a subject diagnosed as having a neurocognitive disorder (NCD) by administering to the subject a transgene encoding one or more triggering receptor expressed on myeloid cells two (TREM2)
proteins (abstract). Lee developed BAC transgenic mice expressing human TREM2 (BAC-TREM2) in microglia. Lee found that elevated TREM2 expression reduced amyloid burden in the 5xFAD mouse model and that elevated TREM2 gene dosage led to improved memory performance in AD models {col 1 para 3). Lee engineered and created a BAC-TREM2-GFP reporter mouse line, which used the |same TREM2 BAC as BAC-TREM2 but express TREM2 protein with a C-terminal GFP fusion.
Lee further teaches that the NCD is a major NCD that interferes with the subject's behavior associated with memory, i.e. normal daily functioning (pg 1042, col 1, para 2, col 2, para 1 "To evaluate whether the neuroprotective phenotypes observed
in 5xFAD/TREM2 mice may correspond to a behavioral improvement, we performed the contextual fear-conditioning test, a hippocampus- dependent memory task that is compromised in 5xFAD mice ... Impressively, unlike the 5xFAD mice that exhibited a robust deficit in this task, the performance of 5xFAD/TREM2 mice is comparable to that of WT controls (Figure 7F). ... we conclude that the BAC-TREM2 transgene is improving both the neuritic pathology and cognitive performance in an amyloid mouse model of AD"). Since Lee teaches that behavioral deficits are ameliorated by overexpressing TREM2 in a mouse model, including a hippocampus-dependent memory task, it
would have been obvious to an artisan of ordinary skill in the art to experiment with using TREM2 overexpression to treat human major NCD, such as the memory deficit in Alzheimer's disease. Lee and Kang teach a method of treating a-subject diagnosed as having a neurocognitive disorder (NCD) the method including administering to the subject a transgene encoding TREM2 operatively linked to a high expression constitutive promoter. Lee further teaches that the NCD could be a mild NCD that is early in disease progression, and thus does not interfere with the subject's normal daily functioning (pg 1045, col 1, para 2 “Our study showed that BAC-TREM2 mice have elevated TREM2 levels as early as 2 months of age ... Thus, we favor a testable model that upregulation of TREM2 levels early in the AD mouse brains, prior to the upregulation of hundreds of other reactive microglial genes, may be more effective in reprogramming the microglial responsivity to ameliorate the disease.").
Lee does not expressly teach a population of cells containing TREM2 operably linked to a high expression constitutive promoter, however, it would have been obvious at the time the invention was field to use such a promoter because Kang teaches transforming cultured cells (and cells in animals) with TREM2 to overexpress the gene (para [0070] "The recombinant expression vector pcDNA3.1/TREM-2 was incorporated to colon cancer cells ... to overexpress TREM-2 gene", para (0023) "a transgenic animal which is transformed with TREM-2 gene to overexpress it", para [0052] "TREM-2 gene may be inserted to a chromosome of an animal according to any conventional transformation methods well known in the art. Kang teaches the use of a retroviral vector, or the like.", note, the vector pcDNA3.1 is commonly used in the art to express mammalian genes in mammalian cells, and comprises a constitutive, high level expression promoter from CMV (see Fig. 1)). Therefore it would have been obvious to an artisan of ordinary skill in the art to use any known method with various methods of creating transgenic expression of TREM2 to treat subjects having a neurocognitive disorder (NCD), including vectors that target a specific population of cells, such as the microglial cells of Lee, using a vector operably linked to a high expression constitutive promoter, such as the CMV promoter of Kang used to drive TREM2 expression.
Lee and Kang do not expressly teach that the high expression constitutive promoter is a Myeloproliferative Sarcoma Virus Enhancer, Negative Control Region Deleted, d1587rev Primer Binding Site Substituted (MND) promoter, however, it would have been obvious to one of ordinary skill in the art at the time the invention was filed to use that promoter because Bluebird teaches that an MND promoter is useful for long term expression in an immune cells. Specifically, Bluebird teaches (abstract "Vector compositions comprising a myeloproliferative sarcoma virus enhancer, negative control region deleted, dI587rev primer-binding site substituted (MND) promoter operably linked to a chimeric antigen receptor (CAR) are provided."), suitable for expression in immune cells (e.g. microglia) (para [0216] “In a particular embodiment, it may be desirable to express a polynucleotide comprising a CAR from a promoter that provides stable and long-term CAR expression in T cells and at sufficient levels to redirect the T cells to cells expressing the target antigen. In a preferred embodiment, the promoter is an MND promoter."). Since
Applicant is directed to pages 12-13 of KSR v Teleflex (500 US 398 2007) “ … the Court has held that a “patent for a combination which only unites old elements with no change in their respective functions . . . obviously withdraws what is already known into the field of its monopoly and diminishes the resources available to skillful men.” Great Atlantic & Pacific Tea Co. v. Supermarket Equipment Corp., 340 U. S. 147, 152 (1950). This is a principal reason for declining to allow patents for what is obvious. The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” “When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one(emphasis added). If a person of ordinary skill can implement a predictable variation, §103 likely bars its patentability. For the same reason, if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond his or her skill.”
"[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); >see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.");< ** In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997).
Accordingly, the claimed invention was prima facie obvious to one of ordinary
skill in the art at the time the invention was made especially in the absence of evidence
to the contrary.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BLAINE LANKFORD whose telephone number is (571)272-0917. The examiner can normally be reached M-Th 8-6:30.
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BLAINE LANKFORD
Examiner
Art Unit 1657
/BLAINE LANKFORD/Primary Examiner, Art Unit 1657