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 .
Claims Status
Claims 47-48,62-63,70, and 76-77 are amended.
Claim 58 is cancelled.
Claims 47-57, and 59-77 are under examination.
Withdrawn Objections
The objection raised against claim 70 is withdrawn in light of claim amendment. Applicant amended the claim by deleting the term “in”.
Withdrawn Rejections
Rejections under- 35 USC § 112
The rejection of claims 47, 63, and 76-77 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of claims amendment. Applicant amended the claims to correct for the antecedent basis issues identified in the previous office action. Accordingly, the rejection is withdrawn.
The rejections of claims 47-77 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is withdrawn in light of Applicant amendment. Applicants amended claims 47-48 to recite “ that the mammalian s-KL has at least 98% amino acid sequence identity to SEQ ID NO: 1 or SEQ ID NO:2 or that the mammalians-KL comprises SEQ ID NO: 1 in which the last 15 amino acids of SEQ ID NO: 1 are removed and replaced with SEQ ID NO: 17”. Applicant also deleted the term “ or functional variant thereof”. Accordingly, the rejection is withdrawn.
Allowable Subject Matter
It should be noted that sequence search was extended to include all of the SEQ ID NOs recited in claim 69. Sequence search did not find any prior art with 100% identity to the
claimed SEQ ID NOs: 17.
Claim Interpretation
The Klotho protein exists in two forms: membrane Klotho (m-KL) and secreted Klotho (s-KL). According to the specification as recited in paragraph [0054] , the term “mammalian s-KL” or a functional variant thereof, refers to the transcript that is generated from alternative splicing of α-klotho human gene. This isoform comprises of the KL1 domain with an approximate weight of about 63 kDa and a specific secretion signal consisting of a 16-amino acid tail that is not found in the full length (i.e. m-KL) transcript or the protolyzed isoform (i.e. p-KL). In other words, it is noted that the claimed mammalian s-KL and its functional variants, encoded by the nucleic acid described herein, exclude the full-length m-KL and p-KL (containing both KL1-KL2 domains) forms of Klotho.
Edited Rejection Necessitated by Claims Amendment.
Applicant’s amendment to claims 47-48 has been considered. Claims 47 and 48 have been amended to incorporate the limitations previously recited in claim 58, including the limitations concerning the sequence of mammalian s-KL. The rejection of claims 47-48, therefore, is edited to incorporate the prior art previously applied to claim 58, together with the prior arts applied to claims 47-48.
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.
Claims 48-57,59-74, and 77 are rejected under 35 U.S.C. 103 as being unpatentable over Abraham et al ( WO 2020/039425 A1), in view of Zeldich et al (Journal of Molecular Neuroscience, 2019), Henricks et al ( Human Molecular, Genetics, 2018), Tarsio et al (WO 2018/098375 A1), Sabater et al ( EP 4046631 A1), Mingozzi et al ( WO 2019/154939 A1),Tabenordbar et al ( Cell, 2021), Grimm et al ( WO 2019/207132 A1), and Xu et al (Biochimica et Biophysica Acta, 2003), as evidenced by Kuro-o et al (Nature, 1997).
Regarding claim 48-54, 59,65- 67,and 77 Abraham et al teach a method for inhibiting tumor growth in a subject in need. The method involves administering a recombinant vector, such as recombinant viral vectors, comprising a muscle-specific promoter (i.e. Desmin promoter) operatively linked to a nucleic acid encoding the secreted isoform of Klotho protein (s-KL). ( See page 3-lines 21-31, page 4-lines 3-4). Furthermore, Abraham et al teach a viral vector with a serotype that has a muscle tropism, such as AAV9 , this reads on step (ii) of the instant claim 48 and claims 59, 65-67. (See claims 1-5, and 14-16). On other words, Abraham et al teach the gene-construct architecture. For example, it expressly identifies the Desmin promoter as a muscle-specific promoter, and provides an exemplary nucleic acid sequence encoding s-KL operably linked to Desmin. Furthermore, Abraham et al teach a viral vector encoding s-KL polypeptide having the amino acid sequence of SEQ ID NO:1 that shares a 100% identity to the claimed SEQ ID NO.1 of instant claim 48. ( See the table including the list of sequences on page 15-16). Thus, Abraham et al teach the claimed viral vector including the claimed s-KL polypeptide and muscle-specific promoter.
Abraham et al teach a recombinant viral construct expressing s-KL for treating cancer. This differs from instant claims, which are directed to the use of the same viral vector but for the treatment of motor impairment.
Zeldich et al demonstrate that Klotho overexpression in the SOD1G93 A , a mouse model of Amyotrophic Lateral Sclerosis (ALS), provides robust neuroprotection. Specifically, Zeldich et al show that Klotho overexpression in SOD1G93A mouse model suppresses the production of proinflammatory cytokines, reduces the expression of neuroinflammatory markers, and prevents neuronal loss, with a more profound effect in the spinal cord than in the motor cortex, thereby delaying the onset and progression of the disease. ( See abstract). Zeldich et al state that “ Our study provides evidence that increased levels of Klotho alleviate ALS-associated pathology in the SOD1 mouse model and may serve as a basis for developing Klotho-based therapeutic strategies for ALS”. ( See abstract). It should be noted that Zeldich et al cite Kuro-o et al; (2005),who also cite Kuro-o et al; 1997, as the source reference for the transgenic animal model . ( See page 266,1st column, 2nd paragraph). According to Kuro-o et al (1997), the transgenic mouse model is generated by overexpressing the full-length cDNA of Klotho (i.e. the membrane-bound isoform ,m-KL). ( See Kuro-o et al , 1997, section “Generation of transgenic mice for rescue” on page 51). This differs from the instant claims, which are directed to the overexpression of secreted splice isoform (i.e. s-KL). However, Zeldich et al expressly characterize Klotho as a potential therapeutic targets for ALS and report that increased Klotho-expression alleviated ALS-associated motor deficits. Thus, Zeldich et al provide a reason for an ordinary skill in the art to consider increasing the level/activity of Klotho in a subject suffering from motor impairment, particularly motor-neuron disease.
In addition, Henricks et al supplement Abraham and Zeldich by demonstrating that Klotho in the mdx mouse model is associated with pro-regenerative activity. As such, culturing myoblast in conditioned media collected from Klotho transgenic bone marrow derived macrophages (BMDMs) (i.e. from the mouse model overexpressing m-Klotho) resulted in substantial increases in myogenic cell counts, which were inhibited by anti-Klotho but not isotype control , when compared to conditioned media from wild-type BMDMs( See Fig.6A). In contrast, conditioned media from Klotho hylomorphic mutant BMDMs did not increase myogenic cell counts, when compared to control cultures (i.e. conditioned media collected from wild-type derived BMDMs) (Fig.6A). Henricks et al also demonstrate that transplantation of Klotho-transgenic bone marrow ( (i.e. bone marrow from the mouse model overexpressing m-Klotho) increased myogenic-cell number and muscle-fiber sized. ( See Fig.5). Accordingly, Henricks teachings suggest that Klotho in general was beneficial not only in neurological/motor-neuron context, as taught by Zeldich et al, but also in the context of skeletal-muscle regeneration and muscle stem-cell expansion.
Furthermore, prior art by Ahrens et al teach that s-KL specifically improves muscle stem-cell function. Ahrens et al demonstrate that loss of Klotho is associated with reduced muscle-stem cell numbers and severely impair skeletal-muscle regeneration. Ahrens et al further demonstrate that the addition of s-KL increased muscle-stem cell cluster formation and restored aspects of stem-cell function. Furthermore, Aherns et al demonstrate that s-KL inhibits excessive Wnt signaling providing a mechanism for the beneficial effect. In other words, the teachings of Ahrens et al would have informed an ordinary skill in the art that the specific s-KL isoform, supplied by Abraham is therapeutically relevant to skeletal-muscle stem cell function and regeneration.
Tarsio et al also supplement the cited prior arts by teaching a nucleic acid construct or vector that encodes a recombinant human s-KL having the amino acid sequence of SEQ ID NO: 41, in which the first 549 amino acids are 100% identical to SEQ ID NO:1 of the instant claim ( as acknowledged in Applicant’s remarks). Tarsio et al also teach that the expression vector can be employed therapeutically to treat muscle atrophy in humans. Furthermore, Tarsio et al suggest using the recombinant vector expressing s-KL to treat patients with ALS disease. (See [0009], [0198], and [0034]). Tarsio et al also state that administration of exogenous s-KL is contemplated for conditions including declines in muscle strength, muscle mass; physical fitness; hands and legs strength; and movement.([0207]). As such, Tarsio et al further provide a motivation for selecting s-KL as a therapeutic payload. Although, Tarsio’s SEQ ID NO.41 additionally includes sequences outside the claimed s-KL portion, the claims do not require that the claimed s-KL be identical to the entirety of Tarsio’s SEQ ID NO.41. Rather, the relevant disclosure of Tarsio is the disclosed human s-KL sequence itself and its therapeutic activity independently of the additional fusion sequences.
Taken together, it would have been prima facie obvious to one with ordinary skill in the art at the time the invention was filed to modify the use of Abraham s-KL gene construct for the treatment of motor impairment, such as the one experienced by ALS patients. Because Abraham et al teach a recombinant viral construct expressing s-KL for treating cancer, but fail to suggest using the construct to treat motor impairment in a subject in need. Zeldich et al provide evidence that increased levels of m-Klotho alleviate ALS-associated pathology in the SOD1 mouse model, and suggest that Klotho-based therapies may be used to improve quality of life, slow disease progression, and extend survival in ALS patients. The teachings of Henricks et al demonstrate that exposing muscle stem cells (i.e. myoblast) to m-Klotho promotes muscle regeneration. Aherns et al identify s-KL is beneficial for skeletal-muscle regeneration, and muscle stem cell function. Further, Tarsio et al identifies s-KL as therapeutically useful for muscle strength, muscle degeneration, and movement-related impairment. Thus, one would have been motivated to use the recombinant vector expressing the s-KL under the control of a muscle-specific promoter, as taught by Abraham, to treat motor impairment in patients with ALS. One would be motivated to employ the recombinant vector of Abraham encoding s-KL as taught by Tarsio and Abraham to specifically deliver the s-KL to the affected muscle rather than using the transgenic mouse model of Zeldich, which would have the inconvenient of having this protein expressed ubiquitously (body and brain). Accordingly, the claimed method represents the predictable application of the known AAV-mediated s-KL gene expression technology of Abraham to a therapeutic application for which Klotho had already been demonstrated to provide beneficial effects, including ALS as taught by Zeldich, skeletal muscle regeneration as taught by Henricks and Ahrens, and muscle strength and movement-related impairments as taught by Tarsio. An ordinary skill in the art would have a reason to employ the s-KL expression vector of Abraham et al, including its muscle-specific Desmin promoter embodiment, for the treatment of motor impairment, and with a reasonable expectation of obtaining the known therapeutic effects of increased Klotho activity. Instant claims are therefore obvious under 35 U.S.C. 103.
Regarding claims 55-56, Abraham et al, in some embodiments, contemplate that the methods comprise systemically administering the viral vector expressing a klotho protein, with parenteral systemic administration. In other embodiments, Abraham et al also contemplate that the method of delivery can be intravenous, intrathecally administered, or via intramuscular injection.
Regarding claim 57, following the discussion above, Abraham et al disclose SEQ ID.NO.1 that shares 100% identity with the claimed SEQ ID NO.1 of instant claim. Tarsio et al further disclose a nucleic acid construct or vector that encodes a recombinant human s-KL having the amino acid sequence of SEQ ID NO: 41, in which the first 549 amino acids are 100% identical to SEQ ID NO:1 of the instant claim. Tarsio et al also expressly teach that the expression vector can be employed therapeutically to treat muscle atrophy in humans. Furthermore, Tarsio et al also suggest using the recombinant vector expressing s-KL to treat patients with ALS disease. (See [0009], [0198], and [0034]). Thus, one would have been motivated to use the recombinant vector expressing the s-KL under the control of a muscle-specific promoter, as taught by Abraham, to treat motor impairment in patients with ALS.
Regarding claims 59 and 60, following the discussion above, the combined teachings of the cited prior art render obvious a viral construct encoding s-KL under the control of Desmin promoter. However, none of the recited prior art specifically teaches viral construct comprising human Desmin promoter, wherein the human Desmin promoter has the nucleic acid sequence of SEQ ID NO:5.
Sabater et al teach an adeno-associated virus (AAVs) vectors comprising of human Desmin promoter (hDES) to drive the expression of isoform 4 of murine Msi2 in muscle cells. It should be noted that Sabater’s construct comprises human Desmin promoter with SEQ ID NO: 69, that share 100% identity with SEQ ID NO:5 of the instant claim. (See page 33-lines 4-21).
Therefore, claims 59-60 are also a product of combining prior art elements according to known methods to yield predictable results, the predictable results being the generation of a recombinant viral construct comprising the human Desmin promoter to drive the expression of s-KL in muscle tissues for the treatment of motor impairment. The combined teachings of the cited prior arts render obvious a viral construct encoding for s-KL under the control of Desmin promoter, but fail to suggest using construct comprising of human Desmin with SEQ ID NO:5. Sabater et al teach a viral construct comprising SEQ ID NO:69, which shares 100% identity with SEQ ID NO:5 of instant claim, to drive the expression of Msi2 in murine muscle cells. Therefore, a person of ordinary skill in the art who had reviewed the cited prior arts could have come across Sabater and immediately noticed the strong possibility of using an expression vector comprising SEQ ID NO:5 would have the predictable results of driving the expression of s-KL specifically into muscle tissue, because Desmin promoter is a muscle-specific promoter.
Regarding claims 62-64, following the discussion above, the combined teachings of the cited prior arts render obvious a viral construct encoding for s-KL under the control of Desmin promoter. However, none of the cited prior art teach gene construct comprising a first and second promoter, wherein the two promoters are different.
Mingozzi et al teach composite transcription regulatory element to drive gene expression in different tissues in a tissue-selective manner. The composite transcription regulatory element comprises hybrid promoters, which are created by fusing at least two different promoters to drive gene expression in different tissues. (See abstract). Mingozzi et al also teach that the second promoter can be a constitutive promoter or selected from a list of tissue-specific promoters that can drive the expression of the transgene into muscle or neurons. ( See claims 1-3). According to Mingozzi et al, using an expression vector comprising of multiple tissue-selective promoters has the advantage of driving high transgene expression in desired tissues in a selective way. (page 3-lines 13-25).
Therefore, claims 62-64 would have been obvious to one of ordinary skill in the art, as there was some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. The combined teachings of Abrahm, Zeldich, Henricks, Ahrens, and Tarsio render obvious a viral construct encoding for s-KL under the control of Desmin promoter, which is a muscle-specific promoter, for the treatment of motor impairment, but they fail to suggest using an expression construct comprising of a second promoter to drive the expression of s-KL in multiple tissues. Mingozzi et al utilize a composite transcription regulatory element to drive gene expression in different tissues in a tissue-selective manner. Thus, one would have been motivated to use a composite nucleic acid comprising of two promoters to drive s-KL expression in different tissues. There would be a reasonable expectation of success, when building the AAV vector, that taking the vector of Abraham, and adding a second promoter that is different from the first promoter, that such modification would drive the expression of s-KL in different tissues in a tissue-selective manner.
Regarding claims 68, following the discussion above, Abraham et al also do not teach AAVmyo vector.
Tabenordbar et al teach an evolved family of RGD-containing AAV capsid variants ( known as AAVmyo) in mice and primates that enable highly effective systemic gene delivery to muscles. Tabenordbar et al also show that these capsids are dependent on integrin heterodimers for transduction across species and enable achieving therapeutic efficacy after systemic administration at low dose.( See abstract).Therefore, the subject matter of claim 68, is also obvious in view of the combination of the cited prior arts and Tabenordbar, as there was some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. The combined teachings of Abrahm, Zeldich, and Henricks, Ahrens, and Tarsio render obvious a viral construct encoding for s-KL under the control of Desmin promoter to treat motor impairment, but fail to suggest using AAVmyo vector. Tabenordbar et al teach an evolved family of RGD-containing AAV capsid variants ( i.e. AAVmyo) in mice and primates that enable highly effective systemic gene delivery to muscles. Thus, one would have been motivated to use AAVmyo vector to enable highly effective systemic s-KL delivery to muscles. There would be a reasonable expectation of success, when constructing the AAV vector, that taking the AAVmyo vector described by Tabenordbar and combining it with the gene construct of Abraham to drive s-KL expression in muscle tissue, that the vector of claim 48 could be successfully synthesized and used for the treatment of motor impairment.
Regarding claims 69-70, Abraham et al do not teach an AAV vector comprising an AAV capsid polypeptide that comprises or consists the amino acid sequence of SEQ ID NO:26.
Grimm et al teach an adeno-associated virus (AAV) capsid polypeptide comprising amino acid sequence of SEQ ID NO:28 which share 100% identity with the instant SEQ ID NO:26. Grimm et al teach that the aforementioned capsid is useful for muscle regeneration or for treating or preventing muscular disease. ( See abstract).
Taken together, the subject matter of claims 69-70, is also obvious in view of the combination of Abraham and Grimm, as there was some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. The combined teachings of Abraham and the previously cited prior arts render obvious a viral construct encoding for s-KL under the control of Desmin promoter to treat motor impairment, but fail to suggest using AAV vector comprising an AAV capsid with SEQ ID NO28. Grimm et al teach an AAV capsid polypeptide that share 100% sequence identity with the instant SEQ ID NO:26 and suggest that an AAV vector comprising the capsid polypeptide would allow for effective delivery to muscle tissue. Thus, one would have been motivated to use an AAV vector comprising an AAV capsid polypeptide comprising of SEQ ID 28, as taught by Grimm et al, to achieve effective systemic s-KL delivery to muscle tissues. There would be a reasonable expectation of success, when building the AAV vector, that taking the AAV capsid polypeptide, as described by Grimm, and Abraham’s gene construct would drive s-KL expression in muscle tissue.
Regarding claims 71-73,following the discussion of claim 47, Abraham et al teach an AAV vector comprising of at least one non-coding regulatory element such as poly A sequence, and 5’ and 3’ inverted terminal repeats. ( See page 8-lines 22-27).
Regarding claims 74, following the discussion above, none of the cited prior art teach the use of an AAv vector comprising the following element: i.e. the WPRE element
Xu et al teach that the utilization of AAv vector for gene therapy can be optimized by including transcriptional and post-transcriptional elements such as a promoter, enhancer, intron, and a poly(A) sequence. As a result, including such elements would improve the expression efficiency of each viral particle, allowing for fewer viral particles to be injected. (See Introduction, 2nd column 1st paragraph page 266). For example, Xu et al teach that inserting the woodchuck hepatitis virus post-transcriptional regulatory (WPRE), a powerful viral enhancer element, between the luciferase gene and the poly(A) in an AAv construct encoding for luciferase, increased luciferase expression 2- to 7-fold in vitro and 2- to 50-fold more in vivo. (See abstract and Material and Methods section 2.1. “ adenovirus vectors” page 267). Hence, the subject matter of claims 74, is also obvious in view of the combination of the Abraham and Xu et al, as there was some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. The combined teachings of cited prior arts render obvious a viral construct encoding for s-KL under the control of Desmin promoter to treat motor impairment, but fail to suggest using AAV vector comprising an enhancer element such as WPRE. Xu et al teach that the inclusion of the WPRE, along with other regulatory elements such as poly A sequence, substantially reduces the number of viral particles that must be injected to achieve a therapeutic level of transgene expression. Thus, one would have been motivated to use an AAV vector comprising WPRE element, as taught by Xu et al, to reduce the number of viral particles that must be injected to achieve a therapeutic level of s-KL expression. There would be a reasonable expectation of success, when building the AAV vector, that taking the WPRE element as described by Xu, and incorporating it in the gene construct of Abraham to drive s-KL expression in muscle tissue, that a lower number of the viral vector of claim 48 is needed to achieve a therapeutic level of transgene expression.
Claims 47-48, and 75-76 are rejected under 35 U.S.C. 103 as being unpatentable over Abraham et al ( WO 2020/039425 A1), in view of Gunther et al ( WO 2016/135295 A1), Mingozzi et al ( WO 2019/154939 A1), and Tarsio et al (WO 2018/098375 A1).
Regarding claims 47,48, and 75-76, the teachings of Abraham et al and Tarsio et al are set forth above, Abraham et al teach a gene construct comprising nucleic acid encoding s-KL ,wherein the expression of s-KL is under the control of a muscle-specific promoter such as Desmin. However, none of the cited previous are teach an isolated cells comprising the said gene construct.
Gunther et al disclose a genetically modified mesenchymal stem cell (MSC) containing s-KL encoding region operably linked to a constitutive promoter. ( See abstract, and page 18-lines 36-39). According to Gunther et al, the genetically modified mesenchymal stem cell can be used as a medicament, with the said cell being administered in a subject in need by introducing a therapeutically effective number of cells into the bloodstream of a subject for the treatment of several diseases, one of which is ALS. ( See page 21-lines 29-30).
Neither Abraham nor Gunther teach an isolated cells expressing the gene construct of claim 47, wherein the cell is a muscle cell including skeletal or striated muscle cell.
The teachings of Mingozzi et al are set forth above.
Mingozzi et al further teach an expression cassette comprising a transgene of interest, wherein the transgene may be a therapeutic transgene that can be used in medicament. Mingozzi et al further teach an isolated cell transformed with the said expression cassette that can also be used to treat motor disease such as ALS, where the isolated cells can be muscle or neuronal cells. ( See page 5 lines 20-31, and page 66 lines 5-17). Mingozzi et also teach that the transformed cells may be delivered to the subject in need thereof via injection in the tissue of interest or in the bloodstream of said subject. ( See page 34 lines 15-22). It should be noted that under the broadest reasonable interpretation, the teachings of Mingozzi et al further include an isolated skeletal or striated muscle.
Taken together, the subject matter of instant claims, are obvious in view of the combination of Abraham, Tarsio, Gunther, and Mingozzi, as there was some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Abraham et al teach a viral construct encoding for s-KL under the control of Desmin promoter to treat cancer, but fail to teach an isolated cells transformed with the said expression construct to treat motor impairment. Gunther et al teach a genetically modified mesenchymal stem cell (MSC) containing s-KL encoding region and clearly suggest the use of the transformed cells in the treatment of diseases such as ALS. Mingozzi et al also teach that muscle or neuronal cells can be transformed with an expression construct encoding a therapeutic transgene and then given to a patient in need via injection in the targeted tissue or in the bloodstream. Thus, one would have been motivated to utilize genetically modified neuronal or muscle cells comprising an expression construct encoding s-KL to treat motor impairment. There would be a reasonable expectation of success, when building a cell therapy, that taking the expression construct of Abraham to genetically modify MSC, muscle, or neuronal cells, that the cell therapy of claims 47-48 could be successfully produced and used in cell therapy.
Response to Arguments
Applicant's arguments filed 05/25/2026 have been fully considered but they are not persuasive.
Applicants argue that they are the first to experimentally demonstrate that s-KL gene therapy or protein therapy can be safely administered to muscle cells to treat motor impairment, and that the present claims possess inventive step over the cited prior arts.
This is not found persuasive, because Applicant’s experimental results do not establish that the claimed subject matter itself would have been non-obvious at the time of the invention. The relevant inquiry under § 103 is whether the claimed subject matter would have been obvious to a person of ordinary skill in the art based on the prior art, rather than whether Applicant was the first to actually perform the claimed experiments. The fact that Applicant conducted experiments confirming that the proposed therapy works does not establish that an ordinary skill in the art lacked a reasonable expectation that the combination would work.
Applicant argues that Abraham is directed to cancer treatment and does not provide a rational for using s-KL to treat motor impairment.
This is not found persuasive, because the rejection does not rely upon Abraham alone. Abraham et al supplies the s-KL expression construct and the muscle-specific promoter. Zeldich separately provide evidence that increased levels of Klotho alleviate ALS-associated pathology in the SOD1 mouse model, and suggest that Klotho-based therapies may be used to improve quality of life, and extend survival in ALS patients. Henricks et al demonstrate that exposing muscle stem cells (i.e. myoblast) to Klotho promotes muscle regeneration. Aherns et al identify s-KL is beneficial for skeletal-muscle regeneration, and muscle stem cell function. Moreover, Tarsio et al identifies s-KL as therapeutically useful for muscle strength, muscle degeneration, and movement-related impairments. Accordingly, Applicants characterization of Abraham in isolation does not address the rejection as actually presented. A reference needs not itself to disclose every advantage or every potential use of the claimed combination when the combined prior arts provide the requisite reason to modify the primary reference. Applicants appear to attack Abraham individually.
Applicants are reminded that 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., 800F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant further argues that Abraham’s disclosure of a muscle-specific promoter was merely a convenient mechanism for delivering s-KL to tumor and that Abraham did not appreciate that muscle expression would improve motor function.
This argument is not found persuasive, because the rejection does not depend on Abraham alone for recognizing the therapeutic use recited in instant claims. Abraham render obvious the claimed muscle-specific expression arrangement. Zeldich, Henricks, Aherns, and Tarsio et al provides the additional therapeutic context in which Klotho expression are employed for the treatment of disease. Again, Applicants appear to attack Abraham individually.
Applicants are reminded that 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., 800F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant argues extensively that the office’s reliance on Zeldich and Kuro-o was factually incorrect because Kuro-o describes a cDNA encoding full length Klotho and a cDNA does not contain introns and therefore cannot itself undergo alternative splicing.
The office finds this argument persuasive only to the extent that the previous rejection relied upon an unsupported inference that expression of full-length Klotho cDNA necessarily results in production of s-KL through alternative splicing. That reasoning is withdrawn. However, withdrawal of that particular reasoning does not overcome the present rejection under U.S.C 103, because the current rejection, as it stands, does not require an inherency theory based upon alternative splicing of the Kuro-o cDNA. Rather, the particular s-KL sequence limitation is expressly addressed by Abraham and Tarsio, as discussed above.
Applicant argues that while amino acids 1-549 of Tarsio's SEQ ID NO: 41 are
100% identical to present SEQ ID NO: 1, Tarsio's SEQ ID NO: 41 is a fusion protein consisting of a total 786 amino acids, linking the 549 amino acids of s-KL to a flexible GGGGS linker and a second proteinaceous moiety, namely transferrin, a Fe domain, or human serum albumin. Applicant argues that Tarsio teaches a fusion protein because the fusion improves half-life; therefore Tarsio does not motivate using s-KL.
This is also not found persuasive because it improperly treats Tarsio as though the rejection requires the bodily incorporation of the entire construct. Tarsio is relied upon for its disclosure of human s-KL and the corresponding amino acid sequence, not for the requirement that the entire fusion construct of Tarsio be incorporated into Abraham construct. The additional fusion partner disclosed by Tarsio does not negate its disclosure of the underlying s-KL sequence. The office agrees with Applicant that the prior art must be considered in a whole, however an ordinary skill in the art is not required to bodily incorporate every feature of the secondary reference into the primary reference. The relevant inquiry is whether the combined teachings would have suggested the claimed arrangement. In other words, the Office does not propose to add Tarsio fusion partner to Abraham’s construct. Rather, Tarsio is relied upon to identify the particular s-KL sequence, while Abraham supplies the expression construct including the muscle-specific promoter. Furthermore, Tarsio et al teach the therapeutic use of the recombinant s-KL, for muscle-related disorders and ALS ( see the rejection above). Add to that, the claim does not require that the nucleic acid encode only s-KL . The claim recites a nucleic acid comprising a sequence encoding mammalian s-KL. Thus, the presence of additional coding sequences, such as Fc domain, does not by itself negate disclosure of nucleic acid containing the claimed Klotho-encoding sequence. To the extent Applicant argue, Abraham et al teach the claimed s-KL polypeptide with 100% identity to claimed SEQ ID NO.1.
Applicant argues Gunther et al’s statement that Klotho is expressed at lower level in skeletal muscle would direct a skilled artisan away from delivering Klotho to muscle tissue.
This is also not found persuasive, because the fact that the expression level of Klotho in muscle tissue does not constitute a teaching away from therapeutically expressing Klotho in muscle tissues. Gunther does not criticize, discredit, or discourage therapeutic Klotho expression in muscle. In fact, Gunther teaches a modified cells expressing Klotho as therapeutic agents and specifically identifies muscle and neurological diseases as potential therapeutic targets. A statement concerning the normal endogenous level of Klotho is not equivalent to a statement that increasing the level of Klotho in that tissue would be ineffective or undesirable. Furthermore, the cited prior arts including Ahrens, Tarsio, Zeldich, and Henricks provide a reason to employ the construct of Abraham for the treatment of muscle impairments. In other words, the observation of Gunther concerning the endogenous level of Klotho in muscle tissue does not negate the motivation supplied by the teachings of the combined prior arts.
As per the MPEP, a prior art disclosure amounts to teaching away when it actually criticizes, discredits, or otherwise discourage the solution claimed.
Applicant further argues that Gunther et al’s ALS disclosure is merely prophetic, and therefore should have little probative value.
This is also not found persuasive, because whether Gunther’s proposed therapeutic application is supported by a working example does not eliminate its disclosure as prior art. Gunther et al expressly teach Klotho expressing cells as a therapeutic agent and identifies ALS among the diseases contemplated for the treatment. The absence of examples does not erase the express teachings or suggestion of using Klotho-expressing cells for ALS. Regarding Applicant arguments that Gunther's "secreted" "soluble" Klotho is exemplified by amino acid sequence of SEQ ID NO: 8 and the corresponding nucleic acid sequence of SEQ ID NO: 3, is not the same as the presently claimed alternative RNA splicing variant of Klotho (s-KL), this also not found persuasive, because sequence alignment between Gunther’s SEQ ID NO.8 and the claimed SEQ ID NO.1 produce a 99.6% sequence identity between the two sequences. ( See Alignment below). It should be noted that instant claim 48 requires only a mammalian s-KL that has at least 98% amino acid sequence identity to SEO ID NO: 1. Therefore, Gunther et al satisfy this limitation. To the extent Applicant argues, the teachings of Abrahm and Tarsio satisfy the claimed specific sequence limitation as discussed above.
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Applicant also argues repeatedly that gene therapy is unpredictable, and that because the field is unpredictable there could not have been a reasonable expectation of success.
This is not found persuasive because the proposed combination does not require the skilled artisan to invent new mechanism of gene therapy. Rather the combined teachings involves a known s-KL expression construct from Abrahm; a known muscle-specific promoter from Abraham; a known human s-KL sequence from Abraham, Tarsio, and Gunther; a known Klotho expressing therapeutic cells from Gunther; a known therapeutic expression cassette from Mingozzi; and clear suggestions and motivations from Zeldich, Henricks, Ahrens, Gunther, and Tarsio. In other words, an ordinary skill in the art had specific prior-arts teachings pointing toward each of the relevant elements. Applicant is reminded that obviousness does not require absolute predictability. Rather, a reasonable expectation of success is sufficient. See MPEP 2143.02 (II).
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 FATIMAH KHALAF MATALKAH whose telephone number is (703)756-5652. The examiner can normally be reached Monday-Friday,7:30 am-4:30 pm EST.
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/FATIMAH KHALAF MATALKAH/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638
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