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 .
Applicant’s amendment field on 12/09/2025 has been entered.
Claims 1-3, 5-7, 10-11, 28-30 and 34-36 are pending in the present application.
Applicant elected previously the invention of Group I, drawn to a method for preventing or treating an age-related disorder or symptoms thereof in a subject. Applicant also elected previously the following species: (i) a nucleic acid comprising a vector or a plasmid comprising a polynucleotide comprising a VEGF encoding polynucleotide sequence; and (ii) hepatic disease is an age-related disorder.
Claims 5-7 and 10 were withdrawn previously from further consideration because they ae directed to non-elected species.
Accordingly, claims 1-3, 11, 28-30 and 34-36 are examined on the merits herein with the above elected species.
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.
Claims 1-3, 11, 28-30 and 34-35 are rejected under 35 U.S.C. 103 as being unpatentable over High et al (US 2003/0130221) in view of Ambrose (Gerontology 63:393-400, June 01, 2017; IDS), Kim et al (Curr Opin Gastroenterol. 31:184-191, 2015; IDS), Furrer et al (PNAS 108:2945-2950, 2011; IDS), Davies et al (British Journal of Cancer 82:1004-1008, 2000), Michaelson et al (WO 2016/092453; IDS) and Deverman et al (US 2017/0166926) for the same reasons already set forth in the Office action dated 06/09/2025 (pages 3-10). The same rejection is restated below.
The instant claims encompass a method for treating an age-related disorder selected from the group consisting of: muscle wasting disease, osteoporosis, pancreatic disease, intestinal disease, neoplastic lesions and hepatic disease (elected species) or symptoms thereof in a mammalian subject, the method comprising administering to said subject a pharmaceutical composition comprising a therapeutically effective amount of a rAAV comprising a polynucleotide comprising a vascular endothelial growth factor (VEGF) encoding polynucleotide sequence and an acceptable carrier, wherein administering said composition once a month to said subject constantly maintains VEGF plasma levels in said subject at 1.5-fold to 3-fold compared to a baseline (e.g., VEGF basal levels in a tissue of the subject, or a standard VEGF plasma level ranging from 50 to 150 pg/ml; dependent claims 11 and 34, respectively), thereby treating the age-related disorder or symptoms thereof in the subject.
With respect to the elected species, High et al already taught a gene therapy method to sustain expression of a therapeutic polypeptide in a mammalian subject (e.g., a human and a mouse), in which method hepatic/liver-directed expression of a therapeutic transgene induces immunological tolerance to the expression product of the therapeutic transgene using at least a recombinant AAV vector/particle comprising a therapeutic transgene operably linked to a liver-specific promoter in a pharmaceutically suitable excipient via intravenous administration (see at least the Abstract; Summary of the Invention; particularly paragraphs 18-25, 37-39, 42-45, 49-53, 57-58, 62-67, 69-70; Figures 1-2; and examples 1-7). High et al stated “The therapeutic polypeptide can be substantially any polypeptide or protein that can elicit a desired therapeutic effect” (paragraph 22); “A therapeutic polypeptide as described herein can be a biologically active peptide, protein fragment or full-length protein that can bring forth a desired therapeutic response” (paragraph 50); “The polynucleotide encoding one or more proteins of interest can be operatively associated with a variety of different promoter/regulator sequences. The promoter/regulator sequences can include a constitutive or inducible promoter, and can be used under the appropriate conditions to direct high level or regulated expression of the gene of interest” (first two sentences of paragraph 57); “Although preferred, it is not necessary that a liver-specific promoter/regulatory region be used. Gene transfer may be effected to hepatocytes via means other than a liver-specific promoter. For example, vector choice and mode of administration may also influence gene transfer to the liver” (paragraph 58); “AAV vectors can be produced in a helper virus-free system, are devoid of any viral gene products, and have reduced immunogenicity compared to other viral vectors” (paragraph 62); and “The methodology of the present invention can be used prophylactically, to minimize the symptoms or risks associated with various diseases or disorders”. Thus, a tolerized subject challenged with a therapeutic nucleic acid (to effect transgenic expression) or a therapeutic polypeptide directly does not exhibit a medically significant neutralizing/inhibitory antibody response and can ideally prevent or ameliorate symptoms associated with a disease or disorder" (paragraph 42). Example 3 demonstrated sustained hF.IX expression for 15 weeks following AAV-EF1alpha-hF.IX (with a constitutive promoter) or AAV-ApoE/hAAT-hF.IX (with a liver-specific promoter) vector administration into three different mouse strains (C57BL/6 mice, BALB/c mice and C3H mice). Even with the use of a constitutive promoter let alone with an inducible promoter, Figure 1B and D-F showed a sustained hF.IX expression level in the plasma is within a narrow range (constant maintenance levels) for some treated C57BL/6, Balb/c and C3H mice between weeks 4-15. Example 4 also demonstrated that in a hemophilia model sustained expression of F.IX in different murine strains following hepatic AAV-mediated gene transfer without a neutralizing anti-hF.IX response that is associated with induction of immune tolerance and that the tolerance induction is antigen-specific and is not broken by challenge (paragraph 98).
High et al did not teach explicitly at least a method of treating an age-related hepatic disorder or symptoms thereof in a mammalian subject by administering to said subject a pharmaceutical composition comprising a therapeutically effective amount of a recombinant adeno-associated virus comprising a polynucleotide encoding VEGF, wherein administering said pharmaceutical composition once a month to said subject constantly maintains VEGF plasma levels in said subject 1-fold to 3-fold compared to a base line, preferably the baseline comprises a standard VEGF plasma level ranging from 50 to 150 pg/ml.
Before the effective filing date of the present application (04/12/2018), Ambrose taught that there is abundant evidence in the literature that a reduced capillary density (CD) and waning levels of angiogenic growth factors (AGFs) such as VEGF, FGF-1, FGF-2 and angiopoietin throughout the body during old age, and these changes influences the physiological state of the aged body and account for its fading functions and possibly the lesser ailments in elderly persons (general muscle weakness, cold intolerance, minor memory lapses, skin wrinkles, and the slow healing of bruises or abrasions in the skin) (see at least the Abstract and Conclusions). Ambrose stated “From this perspective, old age is a deficiency state of AGFs, much like the reduced testosterone levels in elderly males. The above data on reduced CD and AGFs are the basis for the “angiogenesis hypothesis of aging”, whose corollary suggests pro-angiogenesis therapy for symptoms and signs of old age. Several AGFs are now available in recombinant forms (e.g., vascular endothelial growth factor) and have been used safely in animal experiments and in short-term clinical trials” (Abstract). Ambrose also disclosed in Table 2 showing a 1.6-fold decrease (32.3/20.5) in the level of VEGF in parietal cortex of aged rats; a 1.9-fold (1.05/0.55) decrease in the level of VEGF in muscle of aged men; a 2.1-2.3-fold (296/137 or 296/125) decrease in the level of VEGF in aged human mononuclear cells.
Additionally, Kim et al also reviewed aging and liver disease; and they stated “Aging is a condition in which a person gradually loses the ability to maintain homeostasis, due to structural alteration or dysfunction. Aging is a major risk factor for most chronic diseases” and “Aging has been shown to not only enhance the vulnerability to acute liver injury but also increase susceptibility of the fibrotic response. Aging is associated with the severity and poor prognosis of various liver diseases including nonalcoholic fatty liver disease, alcoholic liver disease, hepatitis C, and liver transplantation” (Abstract). Kim et al noted that aging-related changes in liver cells include volume changes, polyploidy (polyploidy nuclei), accumulation of dense bodies (lipofuscin) inside liver cells, a decreased area of smooth endoplasmic reticulum, and a declining number of and dysfunction of mitochondria; and some studies suggested that aging negatively influences the function of the liver by causing a substantial morphological change in the sinusoidal vascular system (section titled “Aging and liver cells”).
Moreover, Furrer et al also reported that age has a significant impact on liver regeneration and animal survival in a well-established model of major hepatectomy in mice; and the data suggest that pseudocapillarization (thickening of the sinusoidal endothelial cells and loss of its porous sieve mimicking capillaries) which is a feature of an old liver acts as a barrier to liver regeneration, and 2,5-dimethoxy-4-iodoamphetamine (DOI) treatment breaks this restraint though an endothelium-dependent mechanism driven by VEGF (Abstract; section titled “Which DOI-dependent pathway mediates opening of fenestrae and hepatocyte proliferation?” on pages 2947-2948; and Figure 4). Furrer et al demonstrated that DOI upregulates VEGF directly without hepatectomy, and serum VEGF levels were raised by DOI treatment alone as shown in Fig. 4B (10 pg/ml and 25 pg/ml, respectively, for without and with DOI treatment alone; a 2.5-fold increase compared to a control baseline). Furrer et al further demonstrated that administration of exogenous recombinant VEGF also enhanced regeneration to the levels of DOI-treated animals (Fig. 4 C and D).
Before the effective filing date of the present application (04/12/2018), Davies et al already assessed plasma levels of VEGF of 19 healthy, “no cancer”, control patients that range from 58.2-235.9 pg/ml with the median value of 125.8 pg/ml (Abstract; and Figure 1). Davies et al also determined plasma VEGF levels in 29 colorectal liver metastasis patients that range from 132.5-284.8 pg/ml with the median value of 180.3 pg/ml (Abstract; and Figure 1).
Additionally, Michaelson et al also taught at least a treatment method for an Alzheimer’s patient having the ApoE4 genotype, comprising administering a recombinant vector encoding and expressing VEGF (e.g., VEGF-A, VEGF-B, VEGF-C, VEGF-D and VEGF-A isoforms such as VEGF121, VEGF145, VEGF165 and VEGF206) into the hippocampus or sub-regions thereof in said patient (Abstract; Summary of the Invention; page 8, lines 25-33; page 11, lines 6-26; Examples 1-5). Michaelson et al also taught that Alzheimer’s disease is characterized by building up of aggregates of the peptide beta-amyloid, and is associated with neuronal and vascular dysfunction (page1, second paragraph). Michaelson et al further stated “According to some embodiments the composition of the present invention is for use by systemic administration, wherein the polynucleotide construct encoding VEGFR agonist is capable of expressing VEGFR agonist specifically in the hippocampus or in a sub-region of the hippocampus” (page 4, lines 28-31.
Moreover, Deverman et al also taught using recombinant AAVs having non-naturally occurring capsid proteins and comprising a nucleic acid sequence encoding a therapeutic protein that includes angiogenic factors such as VEGF121, VEGF165, VEGF-C and VEGF-2 to treat various diseases, and wherein the dosing frequency of the rAAV virus can be administered (e.g., via intravenous) to a subject (e.g., a human) about once a week, about once every two weeks, about once every month, or about once every six month or longer (Abstract; particularly paragraphs [0183], [0211] and [0216]). Deverman et al also taught that a therapeutically effective amount of the rAAV can be administered to the subject prior to, during, or after the subject has developed a disease or disorder (paragraph [0215]).
Accordingly, it would have been obvious for an ordinary skilled artisan to modify the gene therapy method for sustained expression of a therapeutic polypeptide of High et al by also selecting VEGF (e.g., VEGF-A and its isoforms such as VEGF-121, VEGF145, VEGF-165 and VEGF-206) as a therapeutic polypeptide for treating at least an age-related hepatic disorder/disease that is characterized by a reduction in blood vessel density, or symptoms thereof in a mammalian subject in need thereof, by intravenously administering an effective amount of a rAAV comprising a nucleic acid sequence encoding VEGF at a dosage frequency of once a month and to regulate or maintain constantly VEGF plasma levels in said subject 1.5-fold to 3-fold compared to a baseline, including maintaining the VEGF plasma level in a treated human subject at 87 pg/ml, 116 pg/ml, or 145 pg/ml (1.5x, 2x and 2.5x of the minimal basal VEGF plasma level of 58 pg/ml in a healthy human, respectively) that is within the VEGF plasma levels found in healthy and “non-cancer” human patients with the use of an inducible promoter in the rAAV, in light of the teachings of Ambrose, Kim et al, Furrer et al, Davies et al, Michaelson et al and Deverman et al as presented above.
An ordinary skilled artisan would have been motivated to carry out the above modifications because: (i) Ambrose taught that old age is a deficient state of angiogenic growth factors such as VEGF and suggested pro-angiogenesis therapy to treat symptoms and signs of old age, with Table 2 showing a 1.6-fold decrease (32.3/20.5) in the level of VEGF in parietal cortex of aged rats; a 1.9-fold (1.05/0.55) decrease in the level of VEGF in muscle of aged men; a 2.1-2.3-fold (296/137 or 296/125) decrease in the level of VEGF in aged human mononuclear cells; (ii) Kim et al also taught that aging enhances the vulnerability to acute liver injury, the severity and poor prognosis of various liver diseases, and age-related liver changes include accumulation of dense bodies (lipofuscin) in liver cells, declining number of and dysfunction of mitochondria in liver cells and substantial morphological change in the sinusoidal vascular system; (iii) Furrer et al already demonstrated that pseudocapillarization which is a feature of an old liver acts as a barrier to liver regeneration, but DOI treatment breaks this restraint through an endothelium-dependent mechanism driven by VEGF or via administration of exogeneous recombinant VEGF; and the serum VEGF level of 25 pg/ml was raised from 10 pg/mol by the DOI treatment alone (a 2.5-fold increase compared to a control baseline) in mice; (iv) Davies et al already assessed plasma levels of VEGF of 19 healthy, “no cancer”, control patients that range from 58.2-235.9 pg/ml with the median value of 125.8 pg/ml; (v) Michaelson et al already successfully used a recombinant vector encoding and expressing VEGF (e.g., VEGF-A, VEGF-B, VEGF-C, VEGF-D and VEGF-A isoforms such as VEGF121, VEGF145, VEGF165 and VEGF206) for treating an Alzheimer’s patient having the ApoE4 genotype, wherein Alzheimer’s disease is associated with neuronal and vascular dysfunction; and (vi) Deverman et al also taught using recombinant AAVs having non-naturally occurring capsid proteins and comprising a nucleic acid sequence encoding a therapeutic protein that includes angiogenic factors such as VEGF121, VEGF165, VEGF-C and VEGF-2 to treat various diseases, and wherein the dosing frequency of the rAAV virus can be administered (e.g., via intravenous) to a subject (e.g., a human) at least about once every month. Please also note that the primary High reference already exemplified with the use of a constitutive promoter, a sustained hF.IX expression level in the plasma is within a narrow range (constant maintenance levels) for some treated C57BL/6, Balb/c and C3H mice between weeks 4-15; let alone using an inducible promoter for a better regulation or maintaining VEGF plasma levels within the VEGF plasma range found in a healthy subject without a risk of causing cancer. Moreover, due to a sustained therapeutic transgene expression mediated by a rAAV as demonstrated successfully by the High reference, there is no need for more frequent dosing of rAAV into a treated mammalian subject other than about once per month.
An ordinary skilled artisan would have a reasonable expectation of success in light of the teachings of High et al, Ambrose, Kim et al, Furrer et al, Davies et al, Michaelson et al and Deverman et al; coupled with a high level of skill of an ordinary skilled artisan in the relevant art.
The modified method resulting from the combined teachings of High et al, Ambrose, Kim et al, Furrer et al, Davies et al, Michaelson et al and Deverman et al as set forth above is indistinguishable and encompassed by the presently claimed method.
Therefore, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Claim 36 is rejected under 35 U.S.C. 103 as being unpatentable over High et al (US 2003/0130221) in view of Ambrose (Gerontology 63:393-400, June 01, 2017; IDS), Kim et al (Curr Opin Gastroenterol. 31:184-191, 2015; IDS), Furrer et al (PNAS 108:2945-2950, 2011; IDS), Davies et al (British Journal of Cancer 82:1004-1008, 2000), Michaelson et al (WO 2016/092453; IDS) and Deverman et al (US 2017/0166926) as applied to claims 1-3, 11, 28-30 and 34-35 above, and further in view of Gu et al (Digestion 88:235-242, 2013) for the same reasons already set forth in the Office action dated 06/09/2025 (pages 10-11). The same rejection is restated below.
The combined teachings of High et al, Ambrose, Kim et al, Furrer et al, Davies et al, Michaelson et al and Deverman et al were presented above. However, none of the cited references teach or suggest specifically a method for treating an age-related hepatosteatosis.
Before the effective filing date of the present application (04/12/2018), Gu et al already taught that VEGF improves liver regeneration and survival after 90% hepatectomy in a rat model of diet-induced Steatosis (see at least abstract). They found that seven-day survival after subtotal hepatectomy (SH) in rats with diet-induced steatosis was significantly decreased in the FLD group (Male Wistar rats fed with fatty liver-induced diet) compared to controls (fed with normal diet), and in FLD animals treatment of VEGF increased 7-day survival to 90%.
Accordingly, it would have been obvious for an ordinary skilled artisan to further modify the combined teachings of Ambrose, Kim et al, Furrer et al, Davies et al, Michaelson et al and Deverman et al by also treating a subject with an age-related steatosis, in light of the teachings of Gu et al as presented above.
An ordinary skilled artisan would have been motivated to further carry out the above modification because Gu et al already taught successfully that VEGF improves liver regeneration and survival after 90% hepatectomy in a rat model of diet-induced Steatosis, let alone a subject with an age-related hepatosteatosis.
An ordinary skilled artisan would have a reasonable expectation of success in light of the teachings of High et al, Ambrose, Kim et al, Furrer et al, Davies et al, Michaelson et al, Deverman et al and Gu et al; coupled with a high level of skill of an ordinary skilled artisan in the relevant art.
The modified method resulting from the combined teachings of High et al, Ambrose, Kim et al, Furrer et al, Davies et al, Michaelson et al, Deverman et al and Gu et al as set forth above is indistinguishable and encompassed by the presently claimed method.
Therefore, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Response to Arguments
Applicant’s arguments related to the above 103 rejection in the Amendment dated 12/09/2025 (pages 7-10) along with the 1.132 Declaration of Dr. Miriam Grunewald filed on 12/09/2025 have been fully considered, but they are respectfully not found persuasive for the reasons discussed below.
A. Applicant argued basically that the combination of cited references fails to teach or suggest the specific method limitations recited in claim 1, particularly the critical requirement of constantly maintaining VEGF plasma levels at 1.5-fold to 3-fold compared to a baseline through once-monthly administration of the claimed pharmaceutical composition. Applicant also argued that the Examiner’s rejection improperly combines disparate teachings from seven different references without establishing a reasonable motivation to combine these references or a reasonable expectation of success. For example, the primary High reference does not teach or suggest VEGF as a therapeutic protein, treatment of age-related disorders, or the specific dosing regimen and plasma level maintenance requirements recited in claim 1. The secondary references individually address different aspects of aging, liver disease, and VEGF, but none teaches or suggests the specific combination of elements requirements by claim 1, nor does any combination of these references teach or suggest that combination of elements. Particularly, Applicant argued that the Furrer reference merely shows a transient increase in VEGF levels through DOI treatment, not the sustained maintenance of specific VEGF plasma levels through monthly AAV administration as recited in claim 1; and this reference teaches a completely different mechanism of VEGF elevation that does not involve recombinant AAV administration or the sustained maintenance of plasma levels over time. Applicant further argued that the Examiner has not provided adequate reasoning for why a skilled artisan would select VEGF from the broad universe of therapeutic proteins taught by the High reference, combine it with the specific dosing frequency taught by the Deverman reference, and further modifying this combination to achieve the precise plasma level maintenance requirements in claim 1. Moreover, Applicant argued that the Examiner’s assertion that maintaining VEGF plasma levels at 1.5-fold to 3-fold compared to baseline would be obvious is not supported by any of the cited references, which at most restoring VEGF levels to normal baseline levels rather than maintaining them at the specific elevated ranges recited in claim 1.
First, since the above rejections were made under 35 U.S.C. 103 none of the cited references have to teach every limitation of the instant claims. For example, neither the primary High reference nor the Furrer reference have to teach or suggest administering a pharmaceutical composition comprising a therapeutically effective amount of a rAAV comprising a nucleic acid sequence encoding VEGF once a month to a mammalian subject to constantly maintain VEGF plasma levels in the subject 1.5-fold to 3-fold compared to a baseline for treating an age-related hepatic disorder or symptoms thereof in the mammalian subject. It is also apparent that Applicant considered each of the cited references in total isolation one from the others, without considering the specific combination of High et al, Ambrose, Kim et al, Furrer et al, Davies et al, Michaelson et al and Deverman et al. Please refer to the above 103 rejections for details.
Second, the instant claims recite the limitation “wherein administering said pharmaceutical composition once a month to said subject constantly maintains VEGF plasma levels in said subject at 1.5-fold to 3-fold compared to a baseline”. Please note that the limitation encompasses any baseline, including and not necessarily limited to VEGF basal levels in any tissue in any mammalian subject (dependent claim 11), or a standard VEGF plasma level ranging from 50 to 150 pg/ml (dependent claim 34). Thus, the 10 pg/ml serum VEGF level in control old mice in the Furrer reference can be considered as a baseline; or the minimal basal VEGF plasma level of 58 pg/ml in a healthy human patient in the Davies reference can also be considered as a baseline. Moreover, Ambrose already taught that old age is a deficient state of angiogenic growth factors such as VEGF and suggested pro-angiogenesis therapy to treat symptoms and signs of old age, with Table 2 showing a 1.6-fold decrease (32.3/20.5) in the level of VEGF in parietal cortex of aged rats; a 1.9-fold decrease (1.05/0.55) in the level of VEGF in muscle of aged men; a 2.1-2.3-fold decrease (296/137 or 296/125) in the level of VEGF in aged human mononuclear cells (a motivation to select VEGF as a therapeutic protein for treating symptoms or signs of old age, or an age-related disease/disorder). Additionally, Furrer et al already demonstrated that pseudocapillarization which is a feature of an old liver acts as a barrier to liver regeneration, but DOI treatment breaks this restraint through an endothelium-dependent mechanism driven by VEGF or via administration of exogeneous recombinant VEGF; and the serum VEGF level of 25 pg/ml was raised from 10 pg/mol by the DOI treatment alone (a 2.5-fold increase compared to a control baseline) in mice (another motivation to select VEGF as a therapeutic protein for treating an age-related hepatic disease/disorder or symptoms thereof). Deverman et al also taught using recombinant AAVs having non-naturally occurring capsid proteins and comprising a nucleic acid sequence encoding a therapeutic protein that includes angiogenic factors such as VEGF121, VEGF165, VEGF-C and VEGF-2 to treat various diseases, and wherein the dosing frequency of the rAAV virus can be administered (e.g., via intravenous) to a subject (e.g., a human) at least about once every month. Please also note that the primary High reference already exemplified with the use of a constitutive promoter, a sustained hF.IX expression level in the plasma is within a narrow range (constant maintenance levels) for some treated C57BL/6, Balb/c and C3H mice between weeks 4-15; let alone using an inducible promoter for a better regulation or maintaining VEGF plasma levels within the VEGF plasma range found in a healthy subject without a risk of causing cancer. Moreover, due to a sustained therapeutic transgene expression mediated by a rAAV as demonstrated successfully by the High reference, there is also no need for more frequent dosing of rAAV into a treated mammalian subject other than about once per month.
Third, in response to applicant's implicit argument that the examiner has combined an excessive number of references, reliance on a large number of references in a rejection does not, without more, weigh against the obviousness of the claimed invention. See In re Gorman, 933 F.2d 982, 18 USPQ2d 1885 (Fed. Cir. 1991).
Fourth, as set forth in the above modified 103 rejection an ordinary skill in the art would have been motivated to modify the gene therapy method for sustained expression of a therapeutic polypeptide of High et al by also selecting VEGF (e.g., VEGF-A and its isoforms such as VEGF-121, VEGF145, VEGF-165 and VEGF-206) as a therapeutic polypeptide for treating at least an age-related hepatic disorder/disease that is characterized by a reduction in blood vessel density, or symptoms thereof in a mammalian subject in need thereof, by intravenously administering an effective amount of a rAAV comprising a nucleic acid sequence encoding VEGF at a dosage frequency of once a month and to regulate or maintain constantly VEGF plasma levels in said subject 1.5-fold to 3-fold compared to a baseline, including maintaining the VEGF plasma level in a treated human subject at 87 pg/ml, 116 pg/ml, or 145 pg/ml (1.5x, 2x and 2.5x of the minimal basal VEGF plasma level of 58 pg/ml in a healthy human, respectively) that is within the VEGF plasma levels found in healthy and “non-cancer” human patients with the use of an inducible promoter in the rAAV because: (i) Ambrose taught that old age is a deficient state of angiogenic growth factors such as VEGF and suggested pro-angiogenesis therapy to treat symptoms and signs of old age, with Table 2 showing a 1.6-fold decrease (32.3/20.5) in the level of VEGF in parietal cortex of aged rats; a 1.9-fold decrease (1.05/0.55) in the level of VEGF in muscle of aged men; a 2.1-2.3-fold decrease (296/137 or 296/125) in the level of VEGF in aged human mononuclear cells; (ii) Kim et al also taught that aging enhances the vulnerability to acute liver injury, the severity and poor prognosis of various liver diseases, and age-related liver changes include accumulation of dense bodies (lipofuscin) in liver cells, declining number of and dysfunction of mitochondria in liver cells and substantial morphological change in the sinusoidal vascular system; (iii) Furrer et al already demonstrated that pseudocapillarization which is a feature of an old liver acts as a barrier to liver regeneration, but DOI treatment breaks this restraint through an endothelium-dependent mechanism driven by VEGF or via administration of exogeneous recombinant VEGF; and the serum VEGF level of 25 pg/ml was raised from 10 pg/mol by the DOI treatment alone (a 2.5-fold increase compared to a control baseline) in mice; (iv) Davies et al already assessed plasma levels of VEGF of 19 healthy, “no cancer”, control patients that range from 58.2-235.9 pg/ml with the median value of 125.8 pg/ml; (v) Michaelson et al already successfully used a recombinant vector encoding and expressing VEGF (e.g., VEGF-A, VEGF-B, VEGF-C, VEGF-D and VEGF-A isoforms such as VEGF121, VEGF145, VEGF165 and VEGF206) for treating an Alzheimer’s patient having the ApoE4 genotype, wherein Alzheimer’s disease is associated with neuronal and vascular dysfunction; and (vi) Deverman et al also taught using recombinant AAVs having non-naturally occurring capsid proteins and comprising a nucleic acid sequence encoding a therapeutic protein that includes angiogenic factors such as VEGF121, VEGF165, VEGF-C and VEGF-2 to treat various diseases, and wherein the dosing frequency of the rAAV virus can be administered (e.g., via intravenous) to a subject (e.g., a human) at least about once every month. Please also note that the primary High reference already exemplified with the use of a constitutive promoter, a sustained hF.IX expression level in the plasma is within a narrow range (constant maintenance levels) for some treated C57BL/6, Balb/c and C3H mice between weeks 4-15; let alone using an inducible promoter for a better regulation or maintaining VEGF plasma levels within the VEGF plasma range found in a healthy subject without a risk of causing cancer. Moreover, due to a sustained therapeutic transgene expression mediated by a rAAV as demonstrated successfully by the High reference, there is no need for more frequent dosing of rAAV into a treated mammalian subject other than about once per month.
Fifth, with respect to the issue that substantial overexpression of VEGF can have severe undesired consequences please note that the VEGF plasma level in a treated human subject at 87 pg/ml, 116 pg/ml, or 145 pg/ml (1.5x, 2x and 2.5x of the minimal basal VEGF plasma level of 58 pg/ml in a healthy human, respectively) is within the VEGF plasma levels found in healthy and “non-cancer” human patients as reported by the Davies reference. Moreover, it is simply a risk benefit analysis, and it is well within the skill of an ordinary skill in the art to monitor adverse side effects in a treated subject. Wang et al (PLOS ONE 9(10):e110531.doi:10.1371/journal.pone.0110531, 8 pages; 2014) also determined the plasma VEGF concentration in proliferative diabetic retinopathy (PDR) patients to be significantly higher than healthy controls (410.07 ± 174.70 pg/ml vs 114.41 ± 110.99 pg/ml, respectively) (see at least Table 2 and Figure 1). Moreover, please note that the standard under 35 U.S.C. 103 is a “reasonable” expectation of success.
Sixth, it is interesting to note that apart from disclosing a double transgenic mouse whose genome harboring a transgene encoding a tetracycline-regulated transactivator protein (tTA) expressed mostly in the liver and a VEGF163-encoding transgene driven by a tetracycline-responsive promoter, that were kept under tetracycline in sweetened drinking water; and the VEGF-overexpressing transgenic mouse has approximately at most 3-fold higher circulating VEGF levels (a plasma VEGF range of 100-160 pg/mL) over that of a control mouse for an analyzed period of 26 months and the transgenic mouse has increased lifespan and hallmark features of healthy organs and tissues (e.g., pancreas, intestine, liver) compared to a control mouse, the as-filed application does not provide a single working example of a gene therapy method for treating an age-related disorder or symptoms thereof in a mammalian subject as claimed.
B. Applicant argued that there is no clear suggestion or motivation in the prior art that particularly the constantly maintained VEGF level of between 1.5-fold to 3-fold, is the therapeutic window. Paragraph 4 in the 1.132 Declaration of Dr. Grunewald explains that the prior art fails to teach the treatment method of claim 1; and paragraphs 6-9 of the 1.132 Declaration establishing that overexpressing VEGF such that its circulating levels are greater by more than 3-fold compared to baseline, is deleterious and harmful. Thus, Applicant argued that a very particular therapeutic window of up to 3-fold elevated levels of VEGF (compared to baseline) but not more than that is required for therapeutic efficacy and safety for treating age-related disorder recited in claim 1, is unprecedented and clearly cannot be considered as obvious in view of the alleged prior art.
First, based at least on the teachings of Ambrose showing a 1.6-fold decrease (32.3/20.5) in the level of VEGF in parietal cortex of aged rats; a 1.9-fold decrease (1.05/0.55) in the level of VEGF in muscle of aged men; a 2.1-2.3-fold decrease (296/137 or 296/125) in the level of VEGF in aged human mononuclear cells (Table 2); coupled with the teachings of Furrer et al disclosing that pseudocapillarization which is a feature of an old liver acts as a barrier to liver regeneration, but DOI treatment breaks this restraint through an endothelium-dependent mechanism driven by VEGF or via administration of exogeneous recombinant VEGF; and the serum VEGF level of 25 pg/ml was raised from 10 pg/mol by the DOI treatment alone (a 2.5-fold increase compared to a control baseline) in mice; it would have been obvious at least for an ordinary skill to treat an age-related disorder, such as an age-related hepatic disease/disorder or symptoms thereof, in an aged mammalian subject by providing said subject at least a 1.6-fold to 2.5-fold increase in the level of VEGF, including VEGF plasma levels, compared to a baseline such as the VEGF baseline of the aged mammalian subject in need of treatment. Additionally, Davies et al already assessed plasma levels of VEGF of 19 healthy, “no cancer”, control patients that range from 58.2-235.9 pg/ml with the median value of 125.8 pg/ml (Abstract; and Figure 1). Davies et al also determined plasma VEGF levels in 29 colorectal liver metastasis patients that range from 132.5-284.8 pg/ml with the median value of 180.3 pg/ml (Abstract; and Figure 1). Thus, as set forth in the above 103 rejection it would have been obvious for an ordinary skilled artisan to modify the gene therapy method for sustained expression of a therapeutic polypeptide of High et al by also selecting VEGF (e.g., VEGF-A and its isoforms such as VEGF-121, VEGF145, VEGF-165 and VEGF-206) as a therapeutic polypeptide for treating at least an age-related hepatic disorder/disease that is characterized by a reduction in blood vessel density, or symptoms thereof in a mammalian subject in need thereof, by intravenously administering an effective amount of a rAAV comprising a nucleic acid sequence encoding VEGF at a dosage frequency of once a month and to regulate or maintain constantly VEGF plasma levels in said subject 1.5-fold to 3-fold compared to a baseline, including maintaining the VEGF plasma level in a treated human subject at 87 pg/ml, 116 pg/ml, or 145 pg/ml (1.5x, 2x and 2.5x of the minimal basal VEGF plasma level of 58 pg/ml in a healthy human, respectively) that is within the VEGF plasma levels found in healthy and “non-cancer” human patients with the use of an inducible promoter in the rAAV, in light of the teachings of Ambrose, Kim et al, Furrer et al, Davies et al, Michaelson et al and Deverman et al.
Second, the claims do not require that any of the cited prior art has to teach or suggest the 3-fold upper limit since going over this threshold is deleterious, harmful, and clearly should not be contemplated by therapy as discussed in paragraphs 6-9 of the 1.132 Declaration based on generated data from a transgenic mouse model. Rather, as long as the cited prior art teach or suggest any VEGF plasma level that is within the recited window of “1.5-fold to 3-fold compared to a baseline” is sufficient to meet this limitation. The modified method resulting from the combined teachings of High et al, Ambrose, Kim et al, Furrer et al, Davies et al, Michaelson et al and Deverman et al as set forth in the above 103 rejection is indistinguishable and encompassed by the presently claimed method.
Third, please refer to the above 103 rejections for details. Once again, please also note that the standard under 35 U.S.C. 103 is a “reasonable” expectation of success.
Conclusions
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Quang Nguyen, Ph.D., at (571) 272-0776.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s SPE, James Douglas (Doug) Schultz, Ph.D., may be reached at (571) 272-0763.
To aid in correlating any papers for this application, all further correspondence regarding this application should be directed to Group Art Unit 1631; Central Fax No. (571) 273-8300.
Any inquiry of a general nature or relating to the status of this application or proceeding should be directed to (571) 272-0547.
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/QUANG NGUYEN/Primary Examiner, Art Unit 1631