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 .
DETAILED ACTION
Status of Application/Election/Restrictions
Claims 1-17 are pending in this application and under examination in this office action.
Priority
3. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 120 as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of the first paragraph of 35 U.S.C. 112. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, provisional Application No. 62/632505, fails to provide adequate support or enablement in the manner provided by the first paragraph of 35 U.S.C. 112 for one or more claims of this application. The instant application claims a method for treating a neural disease in a subject in need thereof by administering to the subject in need thereof a chimeric polynucleotide molecule comprising: a) a first polynucleotide encoding a propeptide domain of a first polypeptide, and b) a second polynucleotide encoding a second polypeptide of 2-50 amino acids having a modulating activity. The subject matter related to the propeptide domain that is encoded by a polynucleotide set forth in SEQ ID NO: 1 or 2 is not presented in the provisional Application No. 62/643505, filed on February 20, 2018. The subject matter related to SEQ ID NOs: 1-2 was only disclosed in PCT/IL2019/050202 filed on February 20, 2019 (see p.2, [009] of the specification.).
Therefore, the priority for the subject matter related to SEQ ID NOs: 1-2 of the instant application is February 20, 2019.
Claim Objections
4. Claim 10 is objected to because of the following informalities: Claim 10 recites the limitation “wherein said propeptide domain is encoded by a polynucleotide sequence as set forth in SEQ ID NO:1 or SEQ ID NO:2”, which means that the polynucleotide sequence is set forth in SEQ ID NO: 1 or 2. However, based on the sequence listing and p. 11-12, para. [061]-[062] of the specification filed 02/06/2024, the limitation “SEQ ID NO:1 or SEQ ID NO:2” recited in claim 10 is an amino acid sequence. Appropriate correction is required.
Claim Interpretation
5. The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The following is a quotation of pre-AIA 35 U.S.C. 112, sixth paragraph:
An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
This application includes one or more claim limitations that do not use the word “means,” but are nonetheless being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, because the claim limitation(s) uses a generic placeholder that is coupled with functional language without reciting sufficient structure to perform the recited function and the generic placeholder is not preceded by a structural modifier. Such claim limitation(s) is/are: “adopted for combined administration with an anticancer therapy” in claim 16.
Because this/these claim limitation(s) is/are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, it/they is/are being interpreted to cover the corresponding structure described in the specification as performing the claimed function, and equivalents thereof.
If applicant does not intend to have this/these limitation(s) interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, applicant may: (1) amend the claim limitation(s) to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph (e.g., by reciting sufficient structure to perform the claimed function); or (2) present a sufficient showing that the claim limitation(s) recite(s) sufficient structure to perform the claimed function so as to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph.
Claim Rejections - 35 USC § 112
6. The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-17 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
Claims 1-17 are indefinite because:
i. The limitation “a modulating activity” recited in claims 1 and 8-9 renders the claim indefinite because Applicant fails to define the word “a modulating activity” recited in the claims. An agent/molecule can either enhance or inhibit a specific biological activity in a molecule/protein, a cell or a biological system; for example, enhancing synaptic function in neurons or neuronal survival, and subsequently alleviating a neurological disorder associated with synaptic function or neuronal survival or inhibiting neuronal apoptosis or cytotoxicity. Since Applicant has not limited the activity, the cell, the molecule or the disease, the metes and bounds of what is encompassed within the definition of “a modulating activity” cannot be determined. Since the metes and bounds are unknown, a skilled artisan cannot envision what would be considered as “a modulating activity” within the scope of the claim. Thus, the claims are indefinite.
ii. The term “predominantly expressed” in claim 1 or “predominantly” in claim 12 is a relative term which renders the claim indefinite. The term “predominantly expressed” or “predominantly” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Applicant fails to set forth the metes and bounds of what is encompassed within the definition of ““predominantly expressed” or “predominantly””. Since the metes and bounds are unknown, a skilled artisan cannot envision what would be considered as “predominantly expressed” or “predominantly” as recited in the claim, which renders the claims are indefinite.
iii. Claim 7 recite the limitation "said modulating peptide" in line 2 of the claim. There is insufficient antecedent basis for this limitation in the claim.
iv. Claims 6-8 recite the limitations “wherein said modulating peptide is an endogenous peptide”, “wherein said second polypeptide…..is an endogenous peptide”, “wherein said second polypeptide…..is an exogenous peptide” or “wherein said second polypeptide ….. is a synthetic peptide”. These limitations are unclear because the administered chimeric polynucleotide recited in claim is exogenous, not endogenous. It is unclear what the limitation “..said signal peptide… are endogenous to said propeptide” means, what the limitation “…said modulating peptide is an endogenous peptide” means, “..said second polypeptide…is an exogenous peptide means, and “..second polypeptide… is a synthetic peptide” means. Thus, the claims 6-9 are indefinite. For examination purposes, the limitation “wherein said modulating peptide is an endogenous peptide” in claim 7 is interpreted as ““wherein the second polypeptide having a modulating activity is from an endogenous peptide”. The limitation “wherein said second polypeptide having a modulating activity is an endogenous peptide” recited in claim 8 is interpreted as “wherein the second polypeptide having a modulating activity is from an exogenous peptide”.
v. Claims 6-9 recite both narrow and broad limitations. A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 7-9 recite the broad recitation “wherein said modulating peptide is an endogenous peptide”, “wherein …..an exogenous peptide” or “wherein…a synthetic peptide” because “an endogenous peptide’ “an exogenous peptide” or “a synthetic peptide” is not limited to any specific peptide with any activity, and the claims also depends from claim 1 that recites specific peptide with 2-50 amino acids having a modulating activity and encoded by a second polynucleotide, which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
vi. Regarding claim 10, the limitation “wherein said propeptide domain is encoded by a polynucleotide sequence as set forth in SEQ ID NO:1 or SEQ ID NO:2” recited in claim 10 is unclear because the limitation “wherein said propeptide domain is encoded by a polynucleotide sequence as set forth in SEQ ID NO:1 or SEQ ID NO:2” means that the polynucleotide sequence is set forth in SEQ ID NO: 1 or 2. However, SEQ ID NO:1 or 2 recited in claim 10 is an amino acid sequence, not a nucleic acid sequence. The limitation is interpreted as “wherein the propeptide domain is encoded by a polynucleotide sequence and wherein the propeptide domain comprises a sequence as set forth in SEQ ID NO:1 or SEQ ID NO:2”.
vii. Claim limitation “adopted for combined administration with an anticancer therapy” in claim 16 invokes 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. However, the written description fails to disclose the corresponding structure, material, or acts for performing the entire claimed function and to clearly link the structure, material, or acts to the function. the corresponding structure, material, or acts for performing the entire claimed function or why there is no clear linkage between the structure, material, or acts and the function. For example, explain that (i) the disclosure is devoid of any structure that performs the function in the claim, (ii) the structure described in the specification does not perform the entire function in the claim, or (iii) no association between the structure and the function can be found in the specification.
Therefore, the claim is indefinite and is rejected under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph.
Applicant may:
(a) Amend the claim so that the claim limitation will no longer be interpreted as a limitation under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph;
(b) Amend the written description of the specification such that it expressly recites what structure, material, or acts perform the entire claimed function, without introducing any new matter (35 U.S.C. 132(a)); or
(c) Amend the written description of the specification such that it clearly links the structure, material, or acts disclosed therein to the function recited in the claim, without introducing any new matter (35 U.S.C. 132(a)).
If applicant is of the opinion that the written description of the specification already implicitly or inherently discloses the corresponding structure, material, or acts and clearly links them to the function so that one of ordinary skill in the art would recognize what structure, material, or acts perform the claimed function, applicant should clarify the record by either:
(a) Amending the written description of the specification such that it expressly recites the corresponding structure, material, or acts for performing the claimed function and clearly links or associates the structure, material, or acts to the claimed function, without introducing any new matter (35 U.S.C. 132(a)); or
(b) Stating on the record what the corresponding structure, material, or acts, which are implicitly or inherently set forth in the written description of the specification, perform the claimed function. For more information, see 37 CFR 1.75(d) and MPEP §§ 608.01(o) and 2181.
viii. The rest of the claims are indefinite as depending from an indefinite claim.
Claim Rejections - 35 USC § 112
7. The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), fourth paragraph:
Subject to the [fifth paragraph of 35 U.S.C. 112 (pre-AIA )], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 6-9 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claims 6-9 recite the broad recitation “wherein said modulating peptide is an endogenous peptide”, “wherein …..an exogenous peptide” and “wherein…a synthetic peptide” because “an endogenous/exogenous/synthetic peptide” is not limited to any specific peptide with any activity. However, the claims also depend from claim 1 that recites specific peptide with 2-50 amino acids having a modulating activity, which is the narrower statement of the range/limitation. Thus, claims 6-9 fail to further limit the subject matter of the claim upon which it depends. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 112
8. The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for reducing escape latency to the target based on a Morris water maze learning (MWM) behavior test in the naive adult C57BL/6 male mice after injection of a lentiviral vector (LV) encoding TAT-HA-PEP (also called BPEP) (TAT-HA-PEP LV) into the CA1 region of the hippocampus of the naive adult C57BL/6 male mice when compared to control mice injected with LV encoding GFP or treating defined neurodegenerative diseases or neural cell cancer by a defined chimeric polynucleotide encoding a defined chimeric polypeptide as disclosed by Hempstead’799 (US7507799, issued Mar 24, 2009, as in IDS, see the details below under the 102 rejection), does not reasonably provide enablement for a method for treating all forms of neural diseases using a structurally and functionally undefined chimeric polynucleotide recited in instant claim 1 as broadly claimed. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
“There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is ‘undue’. These factors include, but are not limited to: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)”. See MPEP § 2164.01.
Claims 1-17 are directed to a method for treating a neural disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a chimeric polynucleotide comprising a. a first polynucleotide encoding a propeptide domain of a first polypeptide; and b. a second polynucleotide encoding a second polypeptide of 2-50 amino acids having a modulating activity, wherein the propeptide domain is a neural cell predominantly expressed protein precursor, and wherein the first polypeptide and the second polypeptide are not derived from the same gene and are operably linked, thereby treating the neural disease in the subject.
The claims encompass using a structurally and functionally undefined chimeric polynucleotide comprising a. a structurally and functionally undefined first polynucleotide encoding a structurally and functionally undefined propeptide domain of a first structurally and functionally undefined polypeptide; and b. a structurally and functionally undefined second polynucleotide encoding a structurally and functionally undefined second polypeptide of 2-50 amino acids having a undefined modulating activity, wherein the propeptide domain is a neural cell predominantly expressed structurally and functionally undefined protein precursor for treatment of all forms of undefined neural diseases including undefined degenerative diseases, developmental diseases and cancer diseases.
The instant invention is based on findings that i) injection of a lentiviral vector (LV) encoding TAT-HA-PEP (also called BPEP) (TAT-HA-PEP LV) into the CA1 region of the hippocampus of naive adult C57BL/6 male mice resulted in a tendency for shorter escape latency to the target based on a Morris water maze learning (MWM) behavior test in the naive adult C57BL/6 male mice compared to the control mice injected with LV encoding GFP (Figures 8D-E; Example 6), wherein the TAT-HA-PEP has the structure of a specific ProBDNF domain-a specific TAT-a specific HA tag-a specific PEP as shown in Figure 1; ii) a Propeptide comprising or consisting of the amino acid sequence of SEQ ID NO:1 or 2.
Applicant extrapolates the above findings to the claimed method for treating a neural disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a chimeric polynucleotide comprising a) a first polynucleotide encoding a propeptide domain of a first polypeptide; and b) a second polynucleotide encoding a second polypeptide of 2-50 amino acids having a modulating activity, wherein the propeptide domain is a neural cell predominantly expressed protein precursor, and wherein the first polypeptide and the second polypeptide are not derived from the same gene and are operably linked, thereby treating the neural disease in the subject.
Based on the specification, Applicant is enabled for reducing the time of escape latency to the target based on a MWM training behavior test in adult naïve mice after injection of TAT-HA-PEP LV into the CA1 region of the hippocampus of the naïve mice when compared to control mice injected with GFP LV.
The claims are not limited to the agent and method set forth above but also encompass using a structurally and functionally undefined chimeric polynucleotide for treatment of all forms of neural diseases or disorders caused by all possible mechanisms or all forms of degenerative diseases, developmental diseases and cancer diseases caused by all possible mechanisms. The claimed chimeric polynucleotide recited in instant claims comprises a structurally and functionally undefined first polynucleotide encoding a structurally and functionally undefined propeptide domain of a structurally and functionally undefined first polypeptide; and b) a structurally and functionally undefined second polynucleotide encoding a structurally and functionally undefined second polypeptide of 2-50 amino acids having a structurally and functionally undefined modulating activity. However, there is no-well established structural and functional relationship or correlation between the claimed chimeric polynucleotide recited in instant claims in treatment of undefined neural diseases or disorders and the LV encoding the TAT-HA-PEP shown in Example 6 and Figures 8D-E in reducing the time of escape latency to the target in a MWM test in naïve mice or even in treatment of undefined neural diseases or disorders.
The specification fails to provide sufficient guidance to enable one of skill in the art to practice the full scope of the claimed invention without undue experimentation because of the complexity and unpredictability of the undefined neural diseases and the failure of providing support a correlation between the naive adult C57BL/6 male mice and the pathogeneses or causes of all forms of neural diseases or disorders caused by all possible mechanisms including degenerative diseases, developmental diseases and cancer diseases caused by all possible mechanisms in vivo in view of Falkenburger et al. (see p. 261, summary; Falkenburger et al., J. Neural. Transm, 2006; 70:261-268), Tayebati (see p. 106, 1st col, 2nd paragraph, Tayebati, Mech. Ageing Dev. 2006. 127: 100-8) and Sarter (see p. 645, abstract, Sarter, Neurosci. and Biobehav. Rev. 2004. 28: 645-650).
The specification also fails to provide sufficient guidance as to what structural and functional relationship is between the claimed chimeric polynucleotide in treatment of all forms of neural diseases or disorders, and the lentiviral vector encoding TAT-HA-PEP (also called BPEP) (TAT-HA-PEP LV) in reducing the time of escape latency to the target based on a MWM behavior test in the naive adult C57BL/6 male mice compared to the control mice injected with LV encoding GFP (Figures 8D-E; Example 6). Thus, it is unpredictable whether administration of the TAT-HA-PEP LV or the claimed structurally and functionally undefined chimeric polynucleotide to a subject with an undefined neural disease can treat the undefined neural disease including undefined degenerative diseases, undefined developmental diseases and undefined cancer diseases, indicating that undue experimentation is required by a skilled artisan to perform while practicing the claimed invention.
The specification has provided no-well established correlation between the naive adult C57BL/6 male mice and all forms of neural diseases or disorders caused by all possible mechanisms or all forms of degenerative diseases, all forms of developmental diseases and all forms of cancer diseases caused by all possible mechanisms. The molecular mechanisms underlying different forms of neural diseases or disorders, different forms of degenerative diseases, different forms of developmental diseases and different forms of cancer diseases caused by all possible mechanisms are unclear. For example, while several factors and genes have been shown to be involved in pathogenesis of AD including ageing, inflammation and immune response, APP, presenilin1/2, ApoE and genes involved in the amyloid cascade, genes involved in the mitochondrial cascade as taught by Swerdlow (p. 348-344, Swerdlow, Clin. Interv. Ageing 2007; 2:347-359), Atwood et al. (p. 33, abstract; Atwood et al., J. Alzheimer’s Disease; 2015; 47:33-47) and Henstridge et al. (p. 95-103; Henstridge et al., Nat. Rev. Neurosci. 2019; 20: 94-107), molecular mechanisms underlying cognitive dysfunction or dementia in neurodegenerative diseases or Alzheimer’s disease (AD) are still unclear (see p. 94; Henstridge et al. Nat. Rev. Neurosci. 2019; 20: 94-107).
While the skill level in the art is high, the level of predictability is low. Each type of animal models of neural diseases or disorders only reflects part of pathogenesis of the disease as taught by Tayebati (see p. 106, 1st col, 2nd paragraph, Tayebati, Mech. Ageing Dev. 2006. 127: 100-8) and Sarter (see p. 645, abstract, Sarter, Neurosci. and Biobehav. Rev. 2004. 28: 645-650). Applicant obviously intended to treat all forms of neural diseases or disorders caused by all possible mechanisms, or all forms of degenerative diseases, all forms of developmental diseases and all forms of cancer diseases caused by all possible mechanisms. However, the specification has provided no well-established correlation between naive adult C57BL/6 male mice and all forms of neural diseases or disorders caused by all possible mechanisms or all forms of degenerative diseases, all forms of developmental diseases and all forms of cancer diseases caused by all possible mechanisms. The specification fails to establish that different forms of neural diseases or disorders, different forms of degenerative diseases, different forms of developmental diseases and different forms of cancer diseases caused by all possible mechanisms can be treated by the same drugs or same conditions or have the same effects in response to the same drugs or as in naive adult C57BL/6 male mice. The specification provides insufficient guidance to demonstrate that administration of the TAT-HA-PEP LV or the claimed structurally and functionally undefined chimeric polynucleotide can treat all forms of neural diseases or disorders caused by all possible mechanisms or all forms of degenerative diseases, developmental diseases or cancer diseases caused by all possible mechanisms. Thus, it is unpredictable whether one treatment for one specific disorder can be applied to another disorder, indicating that undue experimentation is required by a skilled artisan to perform while practice the claimed invention.
While administration of the LV encoding the TAT-HA-PEP as shown in figure 1 to the CA1 region of the hippocampus of naïve mice can reduce the time of escape latency to the target in a MWM test in the naïve mice, there is no well-established correlation between naive adult C57BL/6 male mice and all forms of neural diseases or disorders. In addition, the art recognizes that fully developed animal models for neurodegenerative disease are still lacking especially for AD, cognitive dysfunction or dementia because of the complexity of the disease and deficiency of characterized cognition (see p. 403, abstract. Anger. Neurotoxicology 1991. 12: 403-13). For example, each type of AD animal models only reflects part of pathogenesis of AD. The animal model of brain amyloidosis induced by Ab can only be used for screening for inhibiting the formation of Ab but not for evaluating the generation of Ab by the effects of b-and g-secretase, which is another molecular mechanism for the pathogenesis of AD (see p. 106, 1st col, 2nd paragraph, Tayebati. Mech. Ageing Dev. 2006. 127: 100-8). The art also recognizes that although the Morris water maze behavioral test is a popular choice used in studies determining effects of learning and memory, the test has been disappointing in the predictive validity of data from animal tests on learning and memory used to discover and characterize drugs for the treatment of cognitive impairment and dementia in clinical testing. The animal tasks generate a high rate of false positive (see p. 646, 2nd col. 2nd paragraph) and the validity of the test itself is also a part of the research process (see p. 645, abstract, Sarter. Neurosci. and Biobehav. Rev. 2004. 28: 645-650). Thus, in order to closely reflect the data obtained from animal models to the real situation of Alzheimer’s disease in humans, it has been proposed that a rodent model should include 1) tests currently used to identify in rodents deficits associated with AD; 2) tests to identify Alzheimer-related signs in patients; and 3) tests that relate to theoretical constructs of human and animal cognition, which should include at least spatial learning and memory (such as Morris Water Maze and Radial Arm Maze), delayed recall match-to-sample, serial response learning, and visual discrimination (such as vertical vs. horizontal stimuli).(see p. 403, abstract. Anger. Neurotoxicology 1991. 12: 403-13). In this case, the specification has provided no-well established correlation between the naive adult C57BL/6 male mice and all forms of neural diseases or disorders caused by all possible mechanisms, all forms of degenerative diseases, all forms of developmental diseases or all forms of cancer diseases caused by all possible mechanisms because there is no any neuronal pathology, or pathogenesis or symptoms in neurons of the CNS or PNS in naive adult C57BL/6 male mice.
The specification also provides no-well established structural and functional relationship or correlation between the claimed chimeric polynucleotide and the LV encoding the TAT-HA-PEP shown in Example 6 and Figures 8D-E in reducing the time of escape latency to the target in a MWM test in naïve mice or even in treatment of undefined neural diseases or disorders.
Based on paragraphs [0051]-[0075] of the published specification, the claimed chimeric polynucleotide includes all possible polynucleotides comprising a polynucleotide that encodes all possible precursor proteins, wherein the chimeric polynucleotide comprises a structurally and functionally undefined first polynucleotide encoding a structurally and functionally undefined propeptide domain of a structurally and functionally undefined first polypeptide and a structurally and functionally undefined second polynucleotide encoding a structurally and functionally undefined second polypeptide of 2-50 amino acids having an undefined modulating activity. However, there is no well-established structural and functional relationship or correlation between the claimed chimeric polynucleotide and a LV encoding proBDNF-TA-HA-PEP (TAT-HA-PEP or BPEP) in reducing the time of escape latency to the target in a MWM test in naïve mice shown in Example 6 or a LV encoding proBDNF-EPE peptide shown in inhibiting ERK translocation in COS7 cells in vitro shown in Example 7 or even in treatment of undefined neural diseases or disorders as instantly claimed.
The structural and functional relationship between the claimed first polynucleotide encoding the claimed propeptide domain of the claimed first polypeptide and proBDNF (SEQ ID NO:1) or proNGF (SEQ ID NO:2) is unknown. The structural and functional relationship between the claimed chimeric polynucleotide and the LV encoding proBDNF-TA-HA-PEP (TAT-HA-PEP or BPEP) or TA-HA-PEP peptide or EPE peptide is unknown. The specification fails to teach what other chimeric polynucleotides, first polynucleotide, propeptide domain, first polypeptide, second polynucleotide, second polypeptide of 2-50 amino acids having a modulating activity are and whether these structurally and functionally undefined chimeric polynucleotides, first polynucleotide, propeptide domain, first polypeptide, second polynucleotide, second polypeptide of 2-50 amino acids having a undefined modulating activity have the activity as in LV-proBDNF-TAT-HA-PEP, LV-proBDNF-EPE or LV-proNGF-EPE. It is known that a single amino acid change on a molecule or protein can abolish the binding ability or activity of the molecule or protein. For example, a substitution of lysine residue by glutamic acid at position 118 of acidic fibroblast growth factor results in a substantial loss of its biological activity including the binding ability to heparin and its receptor (Burgess et al. J of Cell Bio. 1990, 111:2129-2138). Even if an active or binding site were identified in the specification, they may not be sufficient, as the ordinary artisan would not immediately recognize that an active or binding site must assume the proper three-dimensional configuration to be active because conformation is dependent upon surrounding residues; i.e. substitution of non-essential residues can often destroy activity. In addition to a core determinant sequence, the protein-protein interaction also relies on the flanking or noncontiguous residues (see p. 445 the second column, first paragraph, Pawson et al. 2003, Science 300:445-452). The optimal binding motif for a domain is not necessarily suitable for physiological or in vivo interaction. The predictive data always need to be validated by actual analyses in cells (see p. 445, the third column, second paragraph, Pawson et al. 2003, Science 300:445-452). Alaoui-lsmaili teaches that designing a mutein having predictable activities is difficult because of the complexity of the interactions between ligands and receptors (Alaoui-lsmaili et al., Cytokine Growth Factor Rev. 2009; 20:501-507). For example, given the complexity of BMP-BMP receptor interactions, it is difficult to design BMPs with improved affinity and/or specificity for one specific receptor. More importantly, predicting the in vivo biological activity of such altered BMPs remains a challenging undertaking (see p. 502, right col., 2th paragraph). Further, when multiple mutations are introduced, there is even less predictability because Guo et al. teaches that the effects of mutations on protein function are largely additive (see p. 9207, left col., 2th paragraph, Guo et al., PNAS 2004; 101:9205-9210).
The specification fails to teach what other structures/amino acid sequences can or cannot be changed or included in other chimeric polypeptides and encoded by the claimed chimeric polynucleotides comprising a structurally and functionally undefined first polynucleotide encoding a structurally and functionally undefined propeptide domain of a structurally and functionally undefined first polypeptide, and a structurally and functionally undefined second polynucleotide encoding a structurally and functionally undefined second polypeptide of 2-50 amino acids having a undefined modulating activity in order to preserve the activity of LV-proBDNF-TAT-HA-PEP in reducing the time of escape latency to the target in a MWM test in naïve mice shown in Example 6, or the activity of LV-proBDNF-EPE or LV-proNGF-EPE in inhibiting ERK translocation in COS7 cells in vitro shown in Example 7 or even in treatment of undefined neural diseases or disorders as instantly claimed. Thus, a skilled artisan cannot readily know how to make and use the claimed method without undue experimentation.
Therefore, in view of the breadth of the claims, the lack of guidance in the specification, the lack of working example, the unpredictability of inventions, and the current status of the art, undue experimentation would be required by one of skill in the art to perform in order to practice the claimed invention as it pertains to a method for treating a neural disease or disorder by administration of the claimed chimeric polynucleotide to a subject in need thereof.
Claim Rejections - 35 USC § 112
9. Claims 1-17 are rejected 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. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof.
Claims 1-17 are drawn to a method for treating a neural disease or disorder in a subject in need thereof using a chimeric polynucleotide comprising a first polynucleotide encoding a propeptide domain of a first polypeptide and a second polynucleotide encoding a second polypeptide of 5-20 amino acids having a modulating activity, wherein the propeptide domain is a neural cell predominantly expressed protein precursor and the first and second polypeptide are not derived from the same gene and are operably linked.
The claims encompass using a genus of chimeric polynucleotide, a genus of first polynucleotide, a genus of propeptide domain, a genus of first polypeptide, a genus of second polynucleotide, a genus of second polypeptide of 2-50 amino acids having a genus of modulating activity for treating a genus of neural disease or disorder.
Claim 4 encompasses treating a genus of degenerative disease, a genus of developmental disease and a genus of cancer disease. Claims 5-6 encompasses using a genus of signal peptide and a genus of protease/convertase motif. Claims 14-15 encompasses using a genus of anticancer/chemotherapeutic agents. Claims 16-17 encompass encompasses a genus of chemotherapy, radiotherapy, immunotherapy, hormonal therapy, toxin therapy or surgery.
Applicant has not disclosed sufficient species for using the broad genus of chimeric polynucleotide, the broad genus of a first polynucleotide encoding a genus of propeptide domain of a genus of first polypeptide and the broad genus of a second polynucleotide encoding a genus of second polypeptide of 5-20 amino acids having a genus of undefined modulating activity.
The specification only describes: i) a lentiviral vector (LV) comprising a polynucleotide encoding a proBDNF sequence and a cell-penetrating motif TAT, a HA-tag and a peptide sequence (TAT-HA-PEP) (Examples 1-6, figures 1-9) or a LV comprising a polynucleotide encoding a proBDNF sequence and a polynucleotide encoding the sequence of NTS-derived phosphomimetic peptide (EPE peptide) or a LV comprising a polynucleotide encoding proNGF sequence and a polynucleotide encoding the sequence of EPE peptide (Example 7, figures 10-12); ii) injection of a lentiviral vector (LV) encoding TAT-HA-PEP (also called BPEP) (TAT-HA-PEP LV) into the CA1 region of the hippocampus of naive adult C57BL/6 male mice resulted in a tendency for shorter escape latency to the target in a Morris water maze learning (MWM) behavior test compared to control mice injected with LV encoding GFP (Figures 8D-E; Example 6), wherein the TAT-HA-PEP has the structure of the ProBDNF domain-the TAT-the HA tag-the PEP as shown in Figure 1.
However, the claims are not limited to the agents and method set forth above but also encompass using a genus of structurally and functionally undefined chimeric polynucleotides, a genus of structurally and functionally undefined first polynucleotide encoding a genus of structurally and functionally undefined propepetide domain of a genus of structurally and functionally undefine first polypeptide, and a genus of structurally and functionally undefined second polynucleotide encoding a genus of structurally and functionally undefine second polypeptide of 2-50 amino acids having an undefined modulating activity. Claim 4 encompasses treating a genus of undefined degenerative disease, a genus of undefined developmental disease and a genus of undefined cancer disease. Claims 5-6 encompasses using a genus of structurally and functionally undefined signal peptide and a genus of structurally and functionally undefined protease/convertase motif. Claims 14-15 encompasses using a genus of structurally and functionally undefined anticancer/chemotherapeutic agents. Claims 16-17 encompass encompasses a genus of structurally and functionally undefined chemotherapy, radiotherapy, immunotherapy, hormonal therapy, toxin therapy or surgery.
In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant is in possession of and what Applicant is claiming.
M.P.E.P. § 2163 instructs:
An invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function. . . .
An applicant may show possession of an invention by disclosure of drawings or structural chemical formulas that are sufficiently detailed to show that applicant was in possession of the claimed invention as a whole. . . .
An applicant may also show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics.”
This standard has not been met in this case. From the specification, Applicant is in possession of using a LV comprising a polynucleotide encoding proBDNF sequence and a cell-penetrating motif TAT, a HA-tag and a peptide sequence (TAT-HA-PEP) (LV-proBNDF-TAT-HA-PEP) in reducing the time of escape latency to the target in a MWM test in adult naïve mice compared to control mice injected with LV encoding GFP shown in Example 6, or using a LV comprising a polynucleotide encoding proBDNF sequence and a polynucleotide encoding the sequence of NTS-derived phosphomimetic peptide (EPE peptide) (LV-ProBDNF-EPE) or a LV comprising a polynucleotide encoding proNGF sequence and a polynucleotide encoding the sequence of EPE peptide (LV-ProNGF-EPE) in inhibiting ERK translocation in COS7 cells in vitro shown in Example 7, or treating defined neurodegenerative diseases or neural cell cancer by a defined chimeric polynucleotide encoding a defined chimeric polypeptide as disclosed by Hempstead’799 (US7507799).
However, Applicant is not in possession of using the claimed structurally and functionally undefined chimeric polynucleotides encoding structurally and functionally undefined propepetide domains and polypeptides of 2-50 amino acids having an undefined modulating activity for treating a genus of undefined neural diseases or a genus of undefined degenerative disease, a genus of undefined developmental disease or a genus of undefined cancer disease or using a genus of structurally and functionally undefined signal peptide, a genus of structurally and functionally undefined protease/convertase motif, or in combination with using a genus of structurally and functionally undefined anticancer/chemotherapeutic agents or a genus of structurally and functionally undefined chemotherapy, radiotherapy, immunotherapy, hormonal therapy, toxin therapy or surgery for treatment of the claimed genus of undefined neural diseases.
Based on paragraphs [0051]-[0075] of the published specification, the claimed chimeric polynucleotide includes all possible polynucleotides comprising a polynucleotide that encodes all possible precursor proteins comprising a first polynucleotide encoding a propeptide domain of a first polypeptide and a second polynucleotide encoding a second polypeptide of 2-50 amino acids having an undefined modulating activity. However, there is no well-established structural and functional relationship or correlation between the claimed genus of chimeric polynucleotide and a LV encoding proBDNF-TA-HA-PEP (TAT-HA-PEP or BPEP) in reducing the time of escape latency to the target in a MWM test in naïve mice shown in Example 6, or a LV encoding proBDNF-EPE peptide in inhibiting ERK translocation in COS7 cells in vitro shown in Example 7. The structural and functional relationship between the claimed genus of propeptide domain of a first polypeptide and proBDNF is unknown. The structural and functional relationship between the claimed genus of chimeric polynucleotide and the LV encoding the proBDNF-TA-HA-PEP (TAT-HA-PEP or BPEP) or a LV encoding the proBDNF-EPE peptide is unknown.
The specification fails to teach what other chimeric polynucleotides, first polynucleotide, propeptide domain, first polypeptide, second polynucleotide, second polypeptide of 2-50 amino acids having a modulating activity are, and whether these structurally and functionally undefined chimeric polynucleotides, first polynucleotide, propeptide domain, first polypeptide, second polynucleotide, second polypeptide of 2-50 amino acids with a undefined modulating activity have the activity as in LV-proBDNF-TAT-HA-PEP, LV-proBDNF-EPE or LV-proNGF-EPE because a single amino acid change can abolish the binding ability of a molecule. The specification fails to teach what other structures/amino acid sequences can or cannot be changed or included in other chimeric polynucleotides, first polynucleotide, propeptide domain, first polypeptide, second polynucleotide, second polypeptide of 2-50 amino acids having a modulating activity in order to preserve the activity of LV-proBDNF-TAT-HA-PEP in reducing the time of escape latency to the target in a MWM test in naïve mice shown in Example 6 or the activity of LV-proBDNF-EPE or LV-proNGF-EPE in inhibiting ERK translocation in COS7 cells in vitro shown in Example 7 or even in treatment of a genus of undefined neural diseases. There is no description of the conserved regions which are critical to the function of the genus claimed. There is no description of the sites at which variability may be tolerated and there is no information regarding the relation of the structure of other chimeric polynucleotides, first polynucleotide, propeptide domain, first polypeptide, second polynucleotide, and second polypeptide of 2-50 amino acids having a modulating activity to the function of LV-proBDNF-TAT-HA-PEP, LV-proBDNF-EPE or LV-proNGF-EPE.
There is also no structural and functional relationship or correlation between the required function (a propeptide domain present in neural cell of 2-fold greater and a polypeptide of 2-50 amino acids having a modulating activity) and a particular structure or sequence for the first polypeptide comprising the propeptide domain and the second polypeptide of 2-50 amino acids having an undefined modulating activity. The specification fails to teach what other structures/amino acid sequences can or cannot be included/changed in the claimed propeptide domain and the claimed second polypeptide of 2-50 amino acids having an undefined modulating activity or their corresponding chimeric polynucleotides or the claimed promoter polynucleotides for driving the expression of the claimed chimeric polynucleotide in a specific cell.
There is also no structural and functional relationship or correlation between the required function (treating an undefined neural disease) and a particular structure or sequence for the claimed genus of signal peptide, or protease/convertase motif, or in combination with using the claimed genus of structurally and functionally undefined anticancer/chemotherapeutic agents or the claimed genus of structurally and functionally undefined chemotherapy, radiotherapy, immunotherapy, hormonal therapy, toxin therapy or surgery for treatment of the claimed genus of undefined neural diseases.
Furthermore, the prior art does not provide compensatory structural or correlative teachings sufficient to enable one of skill to identify what other chimeric polynucleotides, first polynucleotide, propeptide domain, first polypeptide, second polynucleotide, and second polypeptide of 2-50 amino acids having a modulating activity might be. Since the common characteristics/features of other chimeric polynucleotides, first polynucleotide, propeptide domain, first polypeptide, second polynucleotide, and second polypeptide of 2-50 amino acids having a modulating activity or signal peptide, or protease/convertase motif are unknown, a skilled artisan cannot contemplate the functional correlations of the genus with the claimed invention. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of using the genus of chimeric polynucleotides, first polynucleotide, propeptide domain, first polypeptide, second polynucleotide and second polypeptide of 2-50 amino acids having a modulating activity or in combination with the claimed genus of anticancer/chemotherapeutic agents or chemotherapy, radiotherapy, immunotherapy, hormonal therapy, toxin therapy or surgery for treatment of the genus of undefined neural disease.
Further, as stated in M.P.E.P. § 2163(II)(A)(3), a specification may describe an actual reduction to practice by showing that the inventor constructed an embodiment or performed a process that met all the limitations of the claim and determined that the invention would work for its intended purpose. Cooper v. Goldfarb, 154 F.3d 1321,1327, 47 USPQ2d 1896, 1901 (Fed. Cir. 1998). See also UMC Elecs. Co. v. United States, 816 F.2d 647, 652, 2 USPQ2d 1465, 1468 (Fed. Cir. 1987) (“[T]here cannot be a reduction to practice of the invention ... without a physical embodiment which includes all limitations of the claim.”); Estee Lauder Inc. v. L’Oreal, S.A., 129 F.3d 588, 593, 44 USPQ2d 1610, 1614 (Fed. Cir. 1997) (“[A] reduction to practice does not occur until the inventor has determined that the invention will work for its intended purpose.”); Mahurkar v. C.R. Bard, Inc., 79 F.3d 1572, 1578, 38 USPQ2d 1288, 1291 (Fed. Cir. 1996) (determining that the invention will work for its intended purpose may require testing depending on the character of the invention and the problem it solves).
Whereas a reduction to practice of an uncomplicated invention such as a simple mechanical or electrical device can be achieved by merely providing a diagram of the device wherein one skilled in the relevant art can predict the likely operability of the device by reviewing the diagram, the operability of the claimed invention cannot be predicted by merely reviewing diagrams or illustrations.
To demonstrate the reduction to practice of a method of treating an animal by the administration of the claimed chimeric polynucleotide requires either a working embodiment, a demonstration of operability in the treatment of an art accepted animal model of the condition to be treated wherein that animal model has been shown to be reliably predictive of efficacy in the treatment of the condition, or a demonstration that the therapeutic agent employed therein possesses an activity in which the majority of compounds/chimeric polynucleotides possessing that activity have been shown to be effective in the treatment of that condition. In the instant case, Applicant has provided none of these. Consequently, Applicant has failed to demonstrate possession of the claimed method or even a single species of using the claimed genus of chimeric polynucleotide for treatment of a species of neural disease required thereby as of the earliest effective filing date of the instant application.
With respect to the demonstration of a reduction to practice of a generic invention, M.P.E.P. § 2163(II)(A)(3)(ii) states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus, above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014).
The above position is further supported by In re Clarke, 148 USPQ 665, (CCPA 1966), which held that; “ It appears to be well settled that a single species can rarely, if ever, afford support fora generic claim. In re Soil, 25 C.C.P.A. (Patents) 1309, 97 F.2d 623, 38 USPQ 189; In re Wahlforss et al., 28 C.C.P.A. (Patents) 867,117 F.21 270,48 USPQ 397. The decisions do not however fix any definite number of species which will establish completion of a generic invention and it seems evident therefrom that such number will vary, depending on the circumstances of particular cases. Thus, in the case of a small genus such as halogens, consisting of four species, a reduction to practice of three, or perhaps even two, might serve to complete the generic invention, while in the case of a genus comprising hundreds of species, a considerably large number of reductions to practice would probably be necessary.”
In the instant case, Applicant has failed to demonstrate a reduction to practice of a representative number of species of using the genus of “chimeric polynucleotide” for a method of treating a subject afflicted with a neural disease by the administration of such chimeric polynucleotide thereto. The experimental results described in the specification consist primarily of the characterization of a LV encoding proBDNF-TA-HA-PEP (TAT-HA-PEP or BPEP) in naïve mice compared to control mice treated with a LV encoding GFP based on a MWM training behavior test (shown in Example 6), or a LV encoding proBDNF-EPE peptide in COS7 cells in vitro compared to control cells with no treatment based on ERK translocation (Example 7). Whereas those results demonstrate that injection of a LV encoding proBDNF-TA-HA-PEP (TAT-HA-PEP or BPEP) into the CA1 region of the hippocampus of naive adult C57BL/6 male mice resulted in a tendency for shorter escape latency to the target in a MWM learning behavior test compared to control mice injected with LV encoding GFP (Figures 8D-E; Example 6), they do not support a conclusion that Applicant was in possession of a method of treating a subject afflicted with a neural disease, degenerative disease, developmental disease or cancer by the administration thereto of the claimed genus of chimeric polynucleotide. Those results do not constitute a reduction to practice of a method of treating a subject with a neural disease or disorder because there is no well-established structural and functional relationship or correlation between naive adult C57BL/6 male mice and subjects with the claimed neural disease, degenerative disease, developmental disease or cancer. There is no well-established structural and functional relationship or correlation between reducing the time of escape latency to the target in a MWM learning behavior test in naive adult mice injected with a LV encoding proBDNF-TA-HA-PEP (TAT-HA-PEP or BPEP) into the CA1 region of the hippocampus of the mice compared to control mice injected with LV encoding GFP and treatment of neural disease, degenerative disease, developmental disease or cancer using the claimed genus of chimeric polynucleotide.
Based on MPEP § 2161.01 and §2163, “to satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116”.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
As discussed above, the skilled artisan cannot envision the detailed chemical structure of the encompassed genus of chimeric polynucleotides, first polynucleotide, propeptide domain, first polypeptide, second polynucleotide, second polypeptide of 2-50 amino acids having a modulating activity, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483.
Therefore, the claimed method has not met the written description provision of 35 U.S.C. §112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115). Applicant is directed to the Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, ¶ 1 "Written Description" Requirement. See MPEP § 2161.01 and 2163.
10. 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 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.
Claim Rejections - 35 USC § 102
11. The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-17 are rejected under 35 U.S.C. 102(a)(1) & (a)(2) as being anticipated by Hempstead’799 (US7507799, issued Mar 24, 2009, as in IDS).
Claims 1-17 are drawn to a method for treating a neural disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a chimeric polynucleotide comprising
i) a first polynucleotide encoding a propeptide domain of a first polypeptide; and
ii) a second polynucleotide encoding a second polypeptide of 5-20 amino acids having a modulating activity,
wherein the propeptide domain is a neural cell predominantly expressed protein precursor and wherein the first polypeptide and the second polypeptide are not derived from the same gene and are operably linked, thereby treating the neural disease in the subject.
Hempstead’799 (US7507799) teaches a method of treating neurodegenerative disease, a cancer or a developmental disease in a subject in need thereof (see col.23, line59-col.24, line25), comprising administering to the subject a nucleic acid molecule or a vector encoding a chimeric protein (see col.7-12; col. 17, lines 46-col. 18,line 4), wherein the chimeric protein comprises a pro-domain (i.e. propeptide domain) of a pro-neurotrophin, a connector and a mature neurotrophin domain, wherein the connector is a dipeptide, tetrapeptide… or less than twenty amino acids or a oligopeptides and wherein the connector includes proneurotrophin cleavage site; wherein the pro-domain optionally comprises a signal peptide sequence and a protease motif or is an isoform of prodomain of NGF,BDNF or NT3/4/5; and wherein the pro-neurotrophin includes proBDNF, proNGF, proNT3/4/5 (see col.); and wherein the chimeric protein includes Pro-NGF-connector-mature BDNF, Pro-BDNF-connector-mature NT4/5, Pro-BDNF-connector-mature NGF, Pro-BDNF-connector-mature NT3 and Pro-NT3-connector-mature NGF(see col. 12, lines 50-67), which meets the limitation recited in instant claims 1-17 (see col. 8, line 25 to col.12, line 67; col. 17, line 45-col. 18, line 4; col. 28-29; col. 32-38, examples 1-14; and the sequence alignment below).
Hempstead’799 teaches systemically administering as in claim 2 (see col.25, lines 10-24). Hempstead’799 teach that the chimeric polynucleotide is in a pharmaceutical composition comprising the claimed polynucleotide and a pharmaceutically acceptable carrier as in claim 3 (see col.25, lines 34-56). Hempstead’799 different neural diseases including hypoxic ischemia, stroke, heart attack, microbial/viral infection, meningitis, encephalitis, abscesses, neurodegenerative disease, autoimmune diseases, Alzheimer's Disease, multiple sclerosis, familial dysautonomia, ataxia telangectasia, Charcot-Marie-Tooth disease, Adreno leuko dystrophy, spinal muscular atrophy, Friedriech's ataxia or epilepsy (see col.24, lines 5-25) or medulloblastoma, astrocytoma, malignant dendrocyte or other cancerous condition of a neural cell of the CNS or PNS (see col. 19, lines 10-24; col.25, lines 20-24), which meet the limitations recited in claim 4.
Hempstead’799 teaches that the propeptide domain comprises a signal peptide sequence and a protease/convertase motif as in claim 5, and these signal peptide sequence and protease motif are endogenous to the propeptide as in claim 6 (see col.8, lines 4-13; col. 9, lines 22-61; col. 11, lines 48-59). Hempstead’799 teaches that the modulating peptide is an exogenous peptide or the second polypeptide is an exogenous or synthetic as in claims 7-9 (see col. 17, lines 5-15; col. 17-18). Hempstead’799 teaches that the sequence of the propeptide domain is SEQ ID NO: 43, which is 100% identical to instant SEQ ID NO:1 or is SEQ ID NO:33, which is 99.4% identical to instant SEQ ID NO:2; and thus the propeptide domain disclosed by Hempstead’799 meets the limitation “wherein the propeptide domain is set forth in SEQ ID NO:1 or 2” as in claim 10 because the limitation “set forth in SEQ ID NO:1 or 2” also includes fragments within SEQ ID NO: 1 or 2 (see the sequence alignment below; col.17-18). Hempstead’799 teaches a delivery vector including a viral vector such as adeno-associated virus (AAV), which is a delivery vector, for expression comprising the claimed chimeric polynucleotide as in claim 11 (see col.25, lines 32-41), and wherein the delivery vector including an adenovirus vector comprises a promoter to drive predominant expression in a specific cell including neural cell and sensory neurons and PC 12 cells as in claims 12 (see col. 17, lines 46-col. 18, line 4; col. 19, lines 11; co. 25, lines 16-24; col. 28, lines 51 to col. 29, line 39; col. 34-36, example 6-10; col. 37, examples 13-15). Hempstead’799 teaches that the chimeric polynucleotide is further administered with a parental (i.e.intravenous)or transdermal (i.e. subcutaneous) dosage form as in claim 13 (see col.25, lines 10-56). Hempstead’799 teach that the pharmaceutical composition further comprises at least one anticancer agent such as an inhibitor of Trk activator to induce cell death or a chemotherapeutic agent such as MMP inhibitors as in claims 14-15 (see col.19, lines 53-61; col. 20, line 20-col. 21, line 4) or adopted for combined administration with an anticancer therapy including chemotherapy, radiotherapy, immunotherapy, hormonal therapy, toxin therapy or surgery as in claims 16-17 (see col.19, lines 53-61; col. 20, line 20-col. 21, line 4). Thus, claims 1-17 are anticipated by Hempstead et al. (US7507799).
The sequence search results disclose as follows:
SEQ ID NO:1
US-10-155-886B-43
; Sequence 43, Application US/10155886B
; Patent No. 7507799
; GENERAL INFORMATION:
; APPLICANT: Hempstead, Barbara L.
; APPLICANT: Lee, Ramee
; APPLICANT: Teng, Kenneth K.
; APPLICANT: Kermani, Pouneh
; TITLE OF INVENTION: High Affinity Ligand For p75 Neurotrophin Receptor
; FILE REFERENCE: 955-21 Sequence Nos. 1-68
; CURRENT APPLICATION NUMBER: US/10/155,886B
; CURRENT FILING DATE: 2002-05-24
; NUMBER OF SEQ ID NOS: 118
; SOFTWARE: PatentIn version 3.3
; SEQ ID NO 43
; LENGTH: 128
; TYPE: PRT
; ORGANISM: Homo sapien
US-10-155-886B-43
Query Match 100.0%; Score 128; DB 7; Length 128;
Best Local Similarity 100.0%;
Matches 128; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MTILFLTMVISYFGCMKAAPMKEANIRGQGGLAYPGVRTHGTLESVNGPKAGSRGLTSLA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MTILFLTMVISYFGCMKAAPMKEANIRGQGGLAYPGVRTHGTLESVNGPKAGSRGLTSLA 60
Qy 61 DTFEHVIEELLDEDQKVRPNEENNKDADLYTSRVMLSSQVPLEPPLLFLLEEYKNYLDAA 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 DTFEHVIEELLDEDQKVRPNEENNKDADLYTSRVMLSSQVPLEPPLLFLLEEYKNYLDAA 120
Qy 121 NMSMRVRR 128
||||||||
Db 121 NMSMRVRR 128
SEQ ID NO:2
US-10-155-886B-33
; Sequence 33, Application US/10155886B
; Patent No. 7507799
; GENERAL INFORMATION:
; APPLICANT: Hempstead, Barbara L.
; APPLICANT: Lee, Ramee
; APPLICANT: Teng, Kenneth K.
; APPLICANT: Kermani, Pouneh
; TITLE OF INVENTION: High Affinity Ligand For p75 Neurotrophin Receptor
; FILE REFERENCE: 955-21 Sequence Nos. 1-68
; CURRENT APPLICATION NUMBER: US/10/155,886B
; CURRENT FILING DATE: 2002-05-24
; NUMBER OF SEQ ID NOS: 118
; SOFTWARE: PatentIn version 3.3
; SEQ ID NO 33
; LENGTH: 121
; TYPE: PRT
; ORGANISM: Homo sapien
US-10-155-886B-33
Query Match 99.4%; Score 615; DB 7; Length 121;
Best Local Similarity 99.2%;
Matches 120; Conservative 0; Mismatches 1; Indels 0; Gaps 0;
Qy 1 MSMLFYTLITAFLIGIQAEPHSESNVPAGHTIPQAHWTKLQHSLDTALRRARSAPAAAIA 60
|||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||
Db 1 MSMLFYTLITAFLIGIQAEPHSESNVPAGHTIPQVHWTKLQHSLDTALRRARSAPAAAIA 60
Qy 61 ARVAGQTRNITVDPRLFKKRRLRSPRVLFSTQPPREAADTQDLDFEVGGAAPFNRTHRSK 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ARVAGQTRNITVDPRLFKKRRLRSPRVLFSTQPPREAADTQDLDFEVGGAAPFNRTHRSK 120
Qy 121 R 121
|
Db 121 R 121
Claim Rejections - 35 USC § 103
12. 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.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Hempstead’799 (US7507799, as in IDS) in view of Hempstead’222 (US2013/0115222, published on May 9, 2013, priority Jun 15, 2010).
Hempstead’799 is set forth above but does not teach that the propeptide domain is the amino acid sequence of instant SEQ ID NO:2.
While Hempstead’799 does not explicitly teach that the propeptide domain is the amino acid sequence of instant SEQ ID NO:2, Hempstead’222 (US2013/0115222) teaches this limitation and provides motivation and a reasonable expectation of success. In particular, Hempstead’222 teaches a proNGF domain comprising the amino acid sequence of SEQ ID NO:1, which is 100% identical to instant SEQ ID NO:2 and a vector construct of ProNGF-HA for making a proNGF-HA mice for study (see the sequence alignment below; paragraph [0072]; [0085]-[0087]).
A person of ordinary skill in the art would have recognized that selecting and applying the known sequence of proNGF domain comprising the amino acid sequence of instant SEQ ID NO:2 to the proNGF domain in the chimeric polynucleotide or vector encoding the chimeric protein and method of Hempstead’799 would have yielded the predictable result of treating neurodegenerative diseases or neural cell cancer of the CNS or PNS disclosed by Hempstead’799, and resulted in an improved method.
Using the known sequence of proNGF domain in the Hempstead’799’s chimeric protein and method would generate a chimeric polynucleotide or vector encoding the chimeric protein comprising a pro-domain (i.e. propeptide domain) of a pro-neurotrophin including prodomain of NGF,BDNF or NT3/4/5, a connector and a mature neurotrophin domain for treating neurodegenerative diseases or neural cell cancer of the CNS or PNS disclosed by Hempstead’799, and expand application of the method of Hempstead’799, and would increase patient’s satisfaction with treatment of neurodegenerative diseases or neural cell cancer of the CNS or PNS using a gene therapy encoding the chimeric protein comprising a pro-domain (i.e. propeptide domain) of a pro-neurotrophin including , a connector and a mature neurotrophin domain because a chimeric polynucleotide or a vector encoding the chimeric protein comprising a pro-domain (i.e. propeptide domain) of a pro-neurotrophin including prodomain of NGF,BDNF or NT3/4/5, a connector and a mature neurotrophin domain has been used for treatment of different neurodegenerative diseases and different neural cell cancers of the CNS or PNS as taught by Hempstead’799.
Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select and apply he known sequence of proNGF domain comprising the amino acid sequence of instant SEQ ID NO:2 to the proNGF domain in the chimeric polynucleotide or vector encoding the chimeric protein and the method of Hempstead’799 and yield the predictable result of treating neurodegenerative diseases and different neural cell cancers of the CNS or PNS disclosed by Hempstead’799. It is obvious to combine two prior art elements (i.e. a chimeric polynucleotide comprising a polynucleotide encoding a proNGF domain of proNGF and an oligopeptide disclosed by Hempstead’799 and a proNGF domain comprising the amino acid sequence of instant SEQ ID NO:2 and a vector construct comprising the polynucleotide encoding the proNGF domain disclosed by Hempstead’222) according known methods to yield predictable results or simply substitute one known element (i.e. a proNGF domain comprising the amino acid sequence of instant SEQ ID NO:2 and a vector construct comprising a polynucleotide encoding the proNGF domain disclosed by Hempstead’222) for another (i.e. a chimeric polynucleotide comprising a polynucleotide encoding a proNGF domain of proNGF and an oligopeptide disclosed by Hempstead’799) to obtain predictable results because the results are expected. See KSR International Co. v. Teleflex Inc. 82 USPQ2d 1385 (2007); In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980); In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960); Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992), Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945) and In re Kahn, 441 F.3d 977, 986, 78 USPQ2d 1329, 1335 (Fed. Cir. 2006) and also see MPEP § 2143. 01-I, MPEP § 2144.06 and MPEP §2144.07.
The sequence search results disclose as follows:
SEQ ID NO:2
US-13-704-404-1
; Sequence 1, Application US/13704404
; Publication No. US20130115222A1
; GENERAL INFORMATION
; APPLICANT: Hempstead, Barbara L.
; APPLICANT:Siao, Chia-Jen
; TITLE OF INVENTION: METHODS OF LIMITING MICROVASCULAR DAMAGE FOLLOWING ACUTE MYOCARDIAL ISCHEMIA
; FILE REFERENCE: 26295 (5170-03-US)
; CURRENT APPLICATION NUMBER: US/13/704,404
; CURRENT FILING DATE: 2012-12-14
; PRIOR APPLICATION NUMBER: 61/397,663
; PRIOR FILING DATE: 2010-06-15
; PRIOR APPLICATION NUMBER: PCT/US11/040447
; PRIOR FILING DATE: 2011-06-15
; NUMBER OF SEQ ID NOS: 22
; SOFTWARE: PatentIn version 3.5
; SEQ ID NO 1
; LENGTH: 121
; TYPE: PRT
; ORGANISM: Homo sapiens
US-13-704-404-1
Query Match 100.0%; Score 121; DB 11; Length 121;
Best Local Similarity 100.0%;
Matches 121; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MSMLFYTLITAFLIGIQAEPHSESNVPAGHTIPQAHWTKLQHSLDTALRRARSAPAAAIA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MSMLFYTLITAFLIGIQAEPHSESNVPAGHTIPQAHWTKLQHSLDTALRRARSAPAAAIA 60
Qy 61 ARVAGQTRNITVDPRLFKKRRLRSPRVLFSTQPPREAADTQDLDFEVGGAAPFNRTHRSK 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ARVAGQTRNITVDPRLFKKRRLRSPRVLFSTQPPREAADTQDLDFEVGGAAPFNRTHRSK 120
Qy 121 R 121
|
Db 121 R 121
Conclusion
13. NO CLAIM IS ALLOWED.
14. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Kelman (MS. Thesis, University of Haifa, Sagol Department of Neurobiology, April, 2016) teaches a lentiviral vector (LV) construct comprising a polynucleotide encoding a prodomain of BDNF and a polynucleotide encoding a peptide comprising a cell penetrating motif, a HA-tag, and an inhibitory peptide sequence (TAT-HA-tag-peptide) (BPEP) (p. 29-34; p. 35-45, Figures 20 (A)-30; p. 49-50).
Gaub et al. (PloS One, 2016; 13:e0150601. doi:10.1371/journal.pone.0150601) teaches an expression construct expressing HBpF-proBDNF, wherein the expression construct contains a 6X-His tag, a biotin acceptor peptide (BAP) sequence, a PreScission™ Protease cleavage site and a FLAG-tag attached to the N-terminal part of murine proBDNF (see p. 1, abstract; and p. 3).
US5438121 teaches a BDNF comprising instant SEQ ID NO:1 (see the sequence alignment below).
SEQ ID NO:1
AAR76817
ID AAR76817 standard; protein; 247 AA.
XX
AC AAR76817;
XX
DT 15-JUN-2007 (revised)
DT 25-MAR-2003 (revised)
DT 07-DEC-1995 (first entry)
XX
DE Human prepro-BDNF.
XX
KW Brain derived neurotrophic factor; BDNF; neuron; Alzheimer's disease;
KW trauma; Parkinson's disease; BOND_PC; brain-derived neurotrophic factor;
KW brain-derived neurotrophic factor [Pan troglodytes]; BDNF;
KW brain-derived neurotrophic factor isoform a;
KW brain-derived neurotrophic factor isoform a preproprotein; neurotrophin;
KW brain-derived neurotrophic factor isoform a preproprotein [Homo sapiens];
KW MGC34632; brain-derived neurotrophic factor preproprotein isoform 2;
KW brain-derived neurotrophic factor, isoform CRA_a;
KW brain-derived neurotrophic factor, isoform CRA_a [Homo sapiens];
KW brain-derived neurotrophic factor BDNF2A;
KW brain-derived neurotrophic factor BDNF2A [Homo sapiens];
KW brain-derived neurotrophic factor BDNF2B;
KW brain-derived neurotrophic factor BDNF2B [Homo sapiens];
KW brain-derived neurotrophic factor BDNF2C;
KW brain-derived neurotrophic factor BDNF2C [Homo sapiens];
KW brain-derived neurotrophic factor BDNF3;
KW brain-derived neurotrophic factor BDNF3 [Homo sapiens];
KW brain-derived neurotrophic factor BDNF4;
KW brain-derived neurotrophic factor BDNF4 [Homo sapiens];
KW brain-derived neurotrophic factor BDNF5;
KW brain-derived neurotrophic factor BDNF5 [Homo sapiens];
KW brain-derived neurotrophic factor BDNF6A;
KW brain-derived neurotrophic factor BDNF6A [Homo sapiens];
KW brain-derived neurotrophic factor [Homo sapiens];
KW brain-derived neurotrophic factor precursor;
KW brain-derived neurotrophic factor precursor [Homo sapiens]; GO1657;
KW GO5515; GO6916; GO7406; GO7411; GO7412; GO7631; GO8038; GO8083; GO14047;
KW GO16023; GO16358; GO19222; GO21675; GO42490; GO43523; GO45666; GO46668;
KW GO48167; GO48839; GO5169; GO7399; GO30182.
XX
OS Homo sapiens.
XX
FH Key Location/Qualifiers
FT Active-site 1..128
FT /label= Prepro-peptide
XX
CC PN US5438121-A.
XX
CC PD 01-AUG-1995.
XX
CC PF 25-APR-1991; 91US-00691612.
XX
PR 30-AUG-1989; 89US-00400591.
PR 20-AUG-1990; 90US-00570657.
XX
CC PA (REGE-) REGENERON PHARM INC.
CC PA (PLAC ) MAX PLANCK GES FOERDERUNG WISSENSCHAFTEN.
XX
CC PI Yancopoulos G, Lottspeich F, Leibrock J, Thoenen H, Barde Y;
CC PI Edgar D;
XX
DR WPI; 1995-274920/36.
DR N-PSDB; AAQ93135.
DR PC:NCBI; gi25306253.
DR PC:SWISSPROT; P23560, Q5IS78.
DR PC:BIND; 71005, 80040.
XX
CC PT New brain derived neurotrophic factor proteins sustain survival of CNS
CC PT dopaminergic and cholinergic neurons - used in the diagnosis and
CC PT treatment of neurological disorders, eg. trauma, Alzheimer's disease,
CC PT etc.
XX
CC PS Disclosure; Fig 4B-H; 100pp; English.
XX
CC An adult human retina cDNA library was screened using a probe based on
CC pig BDNF to obtain a clone, phBDNF-C-1, that encoded prepro-BDNF.
CC (Updated on 25-MAR-2003 to correct PF field.)
CC
CC Revised record issued on 15-JUN-2007 : Enhanced with precomputed
CC information from BOND.
XX
SQ Sequence 247 AA;
Query Match 100.0%; Score 655; DB 1; Length 247;
Best Local Similarity 100.0%;
Matches 128; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MTILFLTMVISYFGCMKAAPMKEANIRGQGGLAYPGVRTHGTLESVNGPKAGSRGLTSLA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MTILFLTMVISYFGCMKAAPMKEANIRGQGGLAYPGVRTHGTLESVNGPKAGSRGLTSLA 60
Qy 61 DTFEHVIEELLDEDQKVRPNEENNKDADLYTSRVMLSSQVPLEPPLLFLLEEYKNYLDAA 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 DTFEHVIEELLDEDQKVRPNEENNKDADLYTSRVMLSSQVPLEPPLLFLLEEYKNYLDAA 120
Qy 121 NMSMRVRR 128
||||||||
Db 121 NMSMRVRR 128
WO9728272 teaches a BDNF comprising instant SEQ ID NO:1 (see the sequence alignment below).
SEQ ID NO:1
AAW26238
ID AAW26238 standard; protein; 247 AA.
XX
AC AAW26238;
XX
DT 15-JUN-2007 (revised)
DT 16-MAR-1998 (first entry)
XX
DE Human preproBDNF.
XX
KW Fusion protein; hydrophilic spacer; recombinant; expression system;
KW carboxypeptidase; preproNGF; BOND_PC; brain-derived neurotrophic factor;
KW brain-derived neurotrophic factor [Pan troglodytes]; BDNF;
KW brain-derived neurotrophic factor isoform a;
KW brain-derived neurotrophic factor isoform a preproprotein; neurotrophin;
KW brain-derived neurotrophic factor isoform a preproprotein [Homo sapiens];
KW MGC34632; brain-derived neurotrophic factor preproprotein isoform 2;
KW brain-derived neurotrophic factor, isoform CRA_a;
KW brain-derived neurotrophic factor, isoform CRA_a [Homo sapiens];
KW brain-derived neurotrophic factor BDNF2A;
KW brain-derived neurotrophic factor BDNF2A [Homo sapiens];
KW brain-derived neurotrophic factor BDNF2B;
KW brain-derived neurotrophic factor BDNF2B [Homo sapiens];
KW brain-derived neurotrophic factor BDNF2C;
KW brain-derived neurotrophic factor BDNF2C [Homo sapiens];
KW brain-derived neurotrophic factor BDNF3;
KW brain-derived neurotrophic factor BDNF3 [Homo sapiens];
KW brain-derived neurotrophic factor BDNF4;
KW brain-derived neurotrophic factor BDNF4 [Homo sapiens];
KW brain-derived neurotrophic factor BDNF5;
KW brain-derived neurotrophic factor BDNF5 [Homo sapiens];
KW brain-derived neurotrophic factor BDNF6A;
KW brain-derived neurotrophic factor BDNF6A [Homo sapiens];
KW brain-derived neurotrophic factor [Homo sapiens];
KW brain-derived neurotrophic factor precursor;
KW brain-derived neurotrophic factor precursor [Homo sapiens]; GO1657;
KW GO5515; GO6916; GO7406; GO7411; GO7412; GO7631; GO8038; GO8083; GO14047;
KW GO16023; GO16358; GO19222; GO21675; GO42490; GO43523; GO45666; GO46668;
KW GO48167; GO48839; GO5169; GO7399; GO30182.
XX
OS Homo sapiens.
XX
CC PN WO9728272-A1.
XX
CC PD 07-AUG-1997.
XX
CC PF 31-JAN-1997; 97WO-US001470.
XX
PR 31-JAN-1996; 96US-00595043.
XX
CC PA (TECH-) TECHNOLOGENE INC.
XX
CC PI Sgarlato GD;
XX
DR WPI; 1997-402624/37.
DR N-PSDB; AAT80163.
DR PC:NCBI; gi25306253.
DR PC:SWISSPROT; P23560, Q5IS78.
DR PC:BIND; 71005, 80040.
XX
CC PT Recombinant protein expression system for fusion protein production -
CC PT useful for high quantity production of authentic recombinant proteins.
XX
CC PS Example 6; Page 142-143; 194pp; English.
XX
CC A novel recombinant vector has been developed which comprises a
CC nucleotide sequence encoding a fusion protein. The fusion protein
CC comprises three domains joined together in order, from N-terminus to C-
CC terminus, of a first domain comprising a protein of interest, a second
CC domain comprising a hydrophilic spacer and an affinity domain, each
CC domain comprising amino acid residues. The present sequence represents
CC human preproBDNF, used in example 6 of the present invention. The
CC recombinant vector is used for the production of authentic recombinant
CC proteins of interest. The method of the invention is useful for the
CC expression of fusion proteins capable of isolation by affinity
CC chromatography in pro- or eukaryotic cells. This method allows for the
CC efficient cleavage and generation of authentic proteins of interest that
CC do not contain extraneous (i.e. non-naturally occurring) amino acids
CC
CC Revised record issued on 15-JUN-2007 : Enhanced with precomputed
CC information from BOND.
XX
SQ Sequence 247 AA;
Query Match 100.0%; Score 655; DB 1; Length 247;
Best Local Similarity 100.0%;
Matches 128; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MTILFLTMVISYFGCMKAAPMKEANIRGQGGLAYPGVRTHGTLESVNGPKAGSRGLTSLA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MTILFLTMVISYFGCMKAAPMKEANIRGQGGLAYPGVRTHGTLESVNGPKAGSRGLTSLA 60
Qy 61 DTFEHVIEELLDEDQKVRPNEENNKDADLYTSRVMLSSQVPLEPPLLFLLEEYKNYLDAA 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 DTFEHVIEELLDEDQKVRPNEENNKDADLYTSRVMLSSQVPLEPPLLFLLEEYKNYLDAA 120
Qy 121 NMSMRVRR 128
||||||||
Db 121 NMSMRVRR 128
WO2003016475 teaches a BDNF comprising instant SEQ ID NO:1 (see the sequence alignment below).
SEQ ID NO:1
ADE60746
ID ADE60746 standard; protein; 247 AA.
XX
AC ADE60746;
XX
DT 15-JUN-2007 (revised)
DT 29-JAN-2004 (first entry)
XX
DE Human Protein P23560, SEQ ID NO 6658.
XX
KW Human; pain; neuronal tissue; gene therapy;
KW spinal segmental nerve injury; chronic constriction injury; CCI;
KW spared nerve injury; SNI; Chung; BOND_PC;
KW brain-derived neurotrophic factor;
KW brain-derived neurotrophic factor [Pan troglodytes]; BDNF;
KW brain-derived neurotrophic factor isoform a;
KW brain-derived neurotrophic factor isoform a preproprotein; neurotrophin;
KW brain-derived neurotrophic factor isoform a preproprotein [Homo sapiens];
KW MGC34632; brain-derived neurotrophic factor preproprotein isoform 2;
KW brain-derived neurotrophic factor, isoform CRA_a;
KW brain-derived neurotrophic factor, isoform CRA_a [Homo sapiens];
KW brain-derived neurotrophic factor BDNF2A;
KW brain-derived neurotrophic factor BDNF2A [Homo sapiens];
KW brain-derived neurotrophic factor BDNF2B;
KW brain-derived neurotrophic factor BDNF2B [Homo sapiens];
KW brain-derived neurotrophic factor BDNF2C;
KW brain-derived neurotrophic factor BDNF2C [Homo sapiens];
KW brain-derived neurotrophic factor BDNF3;
KW brain-derived neurotrophic factor BDNF3 [Homo sapiens];
KW brain-derived neurotrophic factor BDNF4;
KW brain-derived neurotrophic factor BDNF4 [Homo sapiens];
KW brain-derived neurotrophic factor BDNF5;
KW brain-derived neurotrophic factor BDNF5 [Homo sapiens];
KW brain-derived neurotrophic factor BDNF6A;
KW brain-derived neurotrophic factor BDNF6A [Homo sapiens];
KW brain-derived neurotrophic factor [Homo sapiens];
KW brain-derived neurotrophic factor precursor;
KW brain-derived neurotrophic factor precursor [Homo sapiens]; GO1657;
KW GO5515; GO6916; GO7406; GO7411; GO7412; GO7631; GO8038; GO8083; GO14047;
KW GO16023; GO16358; GO19222; GO21675; GO42490; GO43523; GO45666; GO46668;
KW GO48167; GO48839; GO5169; GO7399; GO30182.
XX
OS Homo sapiens.
XX
CC PN WO2003016475-A2.
XX
CC PD 27-FEB-2003.
XX
CC PF 14-AUG-2002; 2002WO-US025765.
XX
PR 14-AUG-2001; 2001US-0312147P.
PR 01-NOV-2001; 2001US-0346382P.
PR 26-NOV-2001; 2001US-0333347P.
XX
CC PA (GEHO ) GEN HOSPITAL CORP.
CC PA (FARB ) BAYER AG.
XX
CC PI Woolf C, D'urso D, Befort K, Costigan M;
XX
DR WPI; 2003-268312/26.
DR GENBANK; P23560.
DR PC:NCBI; gi25306253.
DR PC:SWISSPROT; P23560, Q5IS78.
DR PC:BIND; 71005, 80040.
XX
CC PT New composition comprising two or more isolated polypeptides, useful for
CC PT preparing a medicament for treating pain in an animal.
XX
CC PS Claim 1; Page; 1017pp; English.
XX
CC The invention discloses a composition comprising two or more isolated rat
CC or human polynucleotides or a polynucleotide which represents a fragment,
CC derivative or allelic variation of the nucleic acid sequence. Also
CC claimed are a vector comprising the novel polynucleotide, a host cell
CC comprising the vector, a method for identifying a nucleotide sequence
CC which is differentially regulated in an animal subjected to pain and a
CC kit to perform the method, an array, a method for identifying an agent
CC that increases or decreases the expression of the polynucleotide sequence
CC that is differentially expressed in neuronal tissue of a first animal
CC subjected to pain, a method for identifying a compound which regulates
CC the expression of a polynucleotide sequence which is differentially
CC expressed in an animal subjected to pain, a method for identifying a
CC compound that regulates the activity of one or more of the
CC polynucleotides, a method for producing a pharmaceutical composition, a
CC method for identifying a compound or small molecule that regulates the
CC activity in an animal of one or more of the polypeptides given in the
CC specification, a method for identifying a compound useful in treating
CC pain and a pharmaceutical composition comprising the one or more
CC polypeptides or their antibodies. The polynucleotide or the compound that
CC modulates its activity is useful for preparing a medicament for treating
CC pain (e.g. spinal segmental nerve injury (Chung), chronic constriction
CC injury (CCI) and spared nerve injury (SNI)) in an animal (e.g. gene
CC therapy). The sequence presented is a human protein (shown in Table 2 of
CC the specification) which is differentially expressed during pain. Note:
CC The sequence data for this patent did not form part of the printed
CC specification, but was obtained in electronic form directly from WIPO at
CC ftp.wipo.int/pub/published_pct_sequences.
CC
CC Revised record issued on 15-JUN-2007 : Enhanced with precomputed
CC information from BOND.
XX
SQ Sequence 247 AA;
Query Match 100.0%; Score 655; DB 3; Length 247;
Best Local Similarity 100.0%;
Matches 128; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MTILFLTMVISYFGCMKAAPMKEANIRGQGGLAYPGVRTHGTLESVNGPKAGSRGLTSLA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MTILFLTMVISYFGCMKAAPMKEANIRGQGGLAYPGVRTHGTLESVNGPKAGSRGLTSLA 60
Qy 61 DTFEHVIEELLDEDQKVRPNEENNKDADLYTSRVMLSSQVPLEPPLLFLLEEYKNYLDAA 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 DTFEHVIEELLDEDQKVRPNEENNKDADLYTSRVMLSSQVPLEPPLLFLLEEYKNYLDAA 120
Qy 121 NMSMRVRR 128
||||||||
Db 121 NMSMRVRR 128
US2008161543 teaches a BDNF comprising instant SEQ ID NO:1 (see the sequence alignment below) or Human proNGF wild-type protein comprising instant SEQ ID NO:2 (see the sequence alignment below).
SEQ ID NO:1
ASQ16367
ID ASQ16367 standard; protein; 247 AA.
XX
AC ASQ16367;
XX
DT 30-OCT-2008 (first entry)
XX
DE Human brain-derived growth factor, SEQ ID 37.
XX
KW toxin; therapeutic; protein engineering; protein production; cosmetics;
KW neuromuscular disease; neuroprotective; neuropathy; ocular disease;
KW ophthalmological; pain; analgesic; muscle injury; muscular-gen.;
KW musculoskeletal-gen.; vulnerary; headache; cardiovascular disease;
KW cardiovascular-gen.; neuropsychologic disorder; neuroleptic;
KW endocrine disease; endocrine-gen.; cancer; Cytostatic; ear disease;
KW auditory; brain-derived growth factor; BOND_PC;
KW brain-derived neurotrophic factor; BDNF;
KW brain-derived neurotrophic factor isoform a;
KW brain-derived neurotrophic factor isoform a preproprotein; neurotrophin;
KW MGC34632; brain-derived neurotrophic factor preproprotein isoform 2;
KW brain derived neurotrophic factor transcript IIa;
KW brain derived neurotrophic factor transcript IIb;
KW brain derived neurotrophic factor transcript IIc;
KW brain derived neurotrophic factor transcript III;
KW brain derived neurotrophic factor transcript IV;
KW brain-derived neurotrophic factor, isoform CRA_a;
KW brain-derived neurotrophic factor BDNF2A;
KW brain-derived neurotrophic factor BDNF2B;
KW brain-derived neurotrophic factor BDNF2C;
KW brain-derived neurotrophic factor BDNF3;
KW brain-derived neurotrophic factor BDNF4;
KW brain-derived neurotrophic factor BDNF5;
KW brain-derived neurotrophic factor BDNF6A;
KW brain-derived neurotrophic factor precursor; GO1657; GO5515; GO6916;
KW GO7406; GO7411; GO7412; GO7631; GO8038; GO8083; GO14047; GO16023;
KW GO16358; GO19222; GO21675; GO42490; GO43523; GO45666; GO46668; GO48167;
KW GO48839; GO5169; GO7399; GO30182.
XX
OS Homo sapiens.
XX
CC PN US2008161543-A1.
XX
CC PD 03-JUL-2008.
XX
CC PF 06-SEP-2007; 2007US-00817937.
XX
PR 15-MAR-2005; 2005US-0661953P.
PR 15-MAR-2005; 2005US-0662151P.
PR 14-MAR-2006; 2006WO-US009831.
XX
CC PA (STEW/) STEWARD L E.
CC PA (FERN/) FERNANDEZ-SALAS E.
CC PA (FRAN/) FRANCIS J.
CC PA (LISS/) LI S.
CC PA (GILM/) GILMORE M A.
CC PA (AOKI/) AOKI K R.
XX
CC PI Steward LE, Fernandez-Salas E, Francis J, Li S, Gilmore MA;
CC PI Aoki KR;
XX
DR WPI; 2008-L68006/68.
DR PC:NCBI; gi25306253.
DR PC:SWISSPROT; P23560, Q5IS78.
DR PC:BIND; 71005, 80040.
XX
CC PT New modified Clostridial toxin comprises a Clostridial toxin enzymatic
CC PT domain, a Clostridial toxin translocation domain, a targeting domain, and
CC PT a protease cleavage site, useful for producing a polypeptide molecule.
XX
CC PS Example 4; SEQ ID NO 37; 200pp; English.
XX
CC The present invention relates to a novel modified Clostridial toxin which
CC comprises: (a) a Clostridial toxin enzymatic domain capable of executing
CC an enzymatic target modification step of a Clostridial toxin intoxication
CC process; (b) a Clostridial toxin translocation domain capable of
CC executing a translocation step of the Clostridial toxin intoxication
CC process; (c) a targeting domain comprising a polypeptide selected from a
CC glucagon like hormone, a neurohormone, a neuroregulatory cytokine, a
CC neurotrophin, a growth factor, an axon guidance signaling molecule, a
CC sugar binding protein, a ligand that selectively binds a neurexin, a
CC ligand for neurexin-2 alpha, a ligand for neurexin-2 beta, a ligand for
CC neurexin-3 alpha, a ligand for neurexin-3 beta, a WNT, Ng-CAM(L1), NCAM,
CC N-cadherin, Agrin-MUSK, a basement membrane polypeptide, and a variant of
CC any of the polypeptides, such that the targeting domain is capable of
CC executing a cell binding step of the Clostridial toxin intoxication
CC process; and (d) a protease cleavage site, where the cleavage of the
CC protease cleavage site converts the single-chain form of the modified
CC Clostridial toxin into a di-chain form. The modified Clostridial toxin
CC comprises in a linear amino-to-carboxyl single polypeptide order, the
CC Clostridial toxin enzymatic domain, the protease cleavage site, the
CC Clostridial toxin translocation domain, and the targeting domain. The
CC Clostridial toxin enzymatic domain is selected from a botulinum toxin
CC (BoNT)/A enzymatic domain, a BoNT/B enzymatic domain, a BoNT/C1 enzymatic
CC domain, a BoNT/D enzymatic domain, a BoNT/E enzymatic domain, a BoNT/F
CC enzymatic domain, a BoNT/G enzymatic domain and a TeNT enzymatic domain.
CC The protease cleavage site is an endogenous Clostridial toxin di-chain
CC loop protease cleavage site or an exogenous cleavage site, where the
CC endogenous Clostridial toxin di-chain loop protease cleavage site is
CC selected from a BoNT/A di-chain loop protease cleavage site, a BoNT/B di-
CC chain loop protease cleavage site, a BoNT/C1 di-chain loop protease
CC cleavage site, a BoNT/D di-chain loop protease cleavage site, a BoNT/E di
CC -chain loop protease cleavage site, a BoNT/F di-chain loop protease
CC cleavage site, a BoNT/G di-chain loop protease cleavage site and a TeNT
CC di-chain loop protease cleavage site. Moreover, the exogenous protease
CC cleavage site is selected from an enterokinase cleavage site, a Thrombin
CC cleavage site, a Factor Xa cleavage site, a human rhinovirus 3C protease
CC cleavage site, a tobacco etch virus protease cleavage site, a dipeptidyl
CC aminopeptidase cleavage site, a small ubiquitin-like modifier
CC (SUMO)/ubiquitin-like protein-1 (ULP-1) protease cleavage site, and the
CC Clostridial toxin substrate cleavage site. Furthermore, the Clostridial
CC toxin substrate cleavage site is selected from a BoNT/A substrate
CC cleavage site, a BoNT/B substrate cleavage site, a BoNT/C1 substrate
CC cleavage site, a BoNT/D substrate cleavage site, a BoNT/E substrate
CC cleavage site, a BoNT/F substrate cleavage site, a BoNT/G substrate
CC cleavage site and a TeNT substrate cleavage site. The targeting domain
CC comprises a glucagon like hormone selected from a secretin, a glucagon-
CC like peptide, a pituitary adenylate cyclase activating peptide, a
CC glicentin, a glicentin-related polypeptide, an oxyntomodulin, a
CC vasoactive intestinal peptides, a gastric inhibitory polypeptide, a
CC calcitonin-related peptides-visceral gut peptide, and a variant of any
CC the glucagon like hormones. The targeting domain comprises a neurohormone
CC selected from corticotropin-releasing hormone (CCRH) and parathyroid
CC hormone (PTH), and a variant of any of the neurohormones. The targeting
CC domain comprises a neuroregulatory cytokine selected from ciliary
CC neurotrophic factor (CNTF), glycophorin-A (GPA), leukemia inhibitory
CC factor (EIF), an interleukin (IL), oncostatin M, cardiotrophin-1 (CT-1),
CC cardiotrophin-like cytokine (CLC), a neuroleukin, vascular endothelial
CC growth factor (VEGF), an insulin-like growth factors (IGF), an epidermal
CC growth factor (EGF), and a variant of any of the neuroregulatory
CC cytokines. Also described are a polynucleotide mmm molecule encoding the
CC polypeptide and a method for producing the modified Clostridial toxin.
CC The modified Clostridial toxin has enhanced binding activity. It also
CC reduces or prevents unwanted side-effects associated with toxin dispersal
CC into non-targeted areas. The modified Clostridial toxin is useful for
CC producing a polypeptide molecule. It can be used for various clinical,
CC therapeutic, and cosmetic applications, such as, e.g. the treatment of
CC neuromuscular disorders, neuropathic disorders, eye disorders, pain,
CC muscle injuries, headache, cardiovascular diseases, neuropsychiatric
CC disorders, endocrine disorders, cancers, otic disorders, and hyperkinetic
CC facial lines, as well as, other disorders where a Clostridial toxin
CC administration to a mammal can produce a beneficial effect. The present
CC sequence is one such targeting domain of the modified Clostridial toxin.
CC
CC Revised record issued on 13-AUG-2008 : Enhanced with precomputed
CC information from BOND.
XX
SQ Sequence 247 AA;
Query Match 100.0%; Score 655; DB 12; Length 247;
Best Local Similarity 100.0%;
Matches 128; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MTILFLTMVISYFGCMKAAPMKEANIRGQGGLAYPGVRTHGTLESVNGPKAGSRGLTSLA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MTILFLTMVISYFGCMKAAPMKEANIRGQGGLAYPGVRTHGTLESVNGPKAGSRGLTSLA 60
Qy 61 DTFEHVIEELLDEDQKVRPNEENNKDADLYTSRVMLSSQVPLEPPLLFLLEEYKNYLDAA 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 DTFEHVIEELLDEDQKVRPNEENNKDADLYTSRVMLSSQVPLEPPLLFLLEEYKNYLDAA 120
Qy 121 NMSMRVRR 128
||||||||
Db 121 NMSMRVRR 128
SEQ ID NO:2
AQZ63602
ID AQZ63602 standard; protein; 241 AA.
XX
AC AQZ63602;
XX
DT 01-MAY-2008 (first entry)
XX
DE Human proNGF wild-type protein SEQ ID:10.
XX
KW protein stabilization; protein expression; protein purification;
KW site-specific mutagenesis; therapeutic; protein therapy; blastoma;
KW pancreas tumor; breast tumor; neurodegenerative disease; Cytostatic;
KW Neuroprotective; pro nerve growth factor; proNGF; nerve growth factor;
KW BOND_PC; nerve growth factor, beta polypeptide;
KW Nerve growth factor, beta; NGFB; NGF; HSAN5;
KW nerve growth factor, beta subunit; beta-nerve growth factor; Beta-NGF;
KW nerve growth factor, beta polypeptide precursor; MGC161426; MGC161428;
KW nerve growth factor B; nerve growth factor beta polypeptide; GO5057;
KW GO7267; GO7275; GO7422; GO8083; GO19233; GO45664.
XX
OS Homo sapiens.
XX
CC PN US2008050776-A1.
XX
CC PD 28-FEB-2008.
XX
CC PF 25-MAY-2007; 2007US-00807056.
XX
PR 26-MAY-2006; 2006US-0808919P.
XX
CC PA (NEET/) NEET K.
CC PA (PAGA/) PAGADALA P.
XX
CC PI Neet K, Pagadala P;
XX
DR WPI; 2008-C62581/19.
DR PC:NCBI; gi70995319.
DR PC:SWISSPROT; P01138.
XX
CC PT New mutated mammalian stable pro nerve growth factor (proNGF), useful as
CC PT a reagent to study the physiological process of apoptosis of neuronal
CC PT cells, or for treating certain cancers such as neuroblastoma.
XX
CC PS Disclosure; SEQ ID NO 10; 20pp; English.
XX
CC The present invention relates to a novel mutated mammalian stable pro
CC nerve growth factor (proNGF) which is useful as a reagent to study the
CC physiological process of apoptosis of neuronal cells and for the
CC treatment of disorders such as blastoma, pancreas tumor, breast tumor and
CC neurodegenerative disease. The novel mutated mammalian stable proNGF is
CC derived from a wild type mammalian proNGF comprising a pro domain, a
CC mature domain, three dibasic protease sensitive sites with contiguous
CC basic amino acids in the pro domain and each of the basic amino acid
CC residue in each of the dibasic site in the wild type proNGF is replaced
CC by a non-basic amino acid resulting in the mutated proNGF. Independent
CC claims are included for a method for preparing a mutated stable mammalian
CC proNGF from a wild type proNGF; and for a cDNA construct encoding a
CC mutated proNGF. The method of invention comprises subcloning the wild
CC type proNGF cDNA into a cell vector; mutating the cDNA at sites
CC corresponding to each of the dibasic sites to non-basic amino acids to
CC obtain a plasmid with mutated cDNA in the cell vector; transfecting the
CC plasmid or the cell vector containing the plasmid into a host cell to
CC establish a stably transfected cell line which constitutively expresses
CC the cDNA; and culturing the host cell to allow expression of the mutated
CC proNGF. The present sequence is a Human proNGF wild-type protein.
CC
CC Revised record issued on 19-MAR-2008 : Enhanced with precomputed
CC information from BOND.
XX
SQ Sequence 241 AA;
Query Match 100.0%; Score 619; DB 12; Length 241;
Best Local Similarity 100.0%;
Matches 121; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MSMLFYTLITAFLIGIQAEPHSESNVPAGHTIPQAHWTKLQHSLDTALRRARSAPAAAIA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MSMLFYTLITAFLIGIQAEPHSESNVPAGHTIPQAHWTKLQHSLDTALRRARSAPAAAIA 60
Qy 61 ARVAGQTRNITVDPRLFKKRRLRSPRVLFSTQPPREAADTQDLDFEVGGAAPFNRTHRSK 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ARVAGQTRNITVDPRLFKKRRLRSPRVLFSTQPPREAADTQDLDFEVGGAAPFNRTHRSK 120
Qy 121 R 121
|
Db 121 R 121
WO2015091130 teaches a BDNF comprising instant SEQ ID NO:1 (see the sequence alignment below).
SEQ ID NO:1
BCB52227
ID BCB52227 standard; protein; 247 AA.
XX
AC BCB52227;
XX
DT 13-AUG-2015 (first entry)
XX
DE Human wild-type pre-pro-BDNF protein, SEQ ID 20.
XX
KW BDNF protein; Brain derived neurotrophic factor ligand; furin;
KW glycosylation; protein engineering; protein production;
KW recombinant protein; substrate.
XX
OS Homo sapiens.
XX
FH Key Location/Qualifiers
FT Cleavage-site 125..128
FT /note= "Furin cleavage site"
FT Protein 129..247
FT /label= Mature_protein
FT /note= "BDNF protein"
XX
CC PN WO2015091130-A1.
XX
CC PD 25-JUN-2015.
XX
CC PF 10-DEC-2014; 2014WO-EP077137.
XX
PR 20-DEC-2013; 2013EP-00198733.
XX
CC PA (HOFF ) HOFFMANN LA ROCHE & CO AG F.
CC PA (HOFF ) HOFFMANN LA ROCHE INC.
XX
CC PI Kopetzki E, Neumann S, Maier P, Huelsmann PM, Lorenz S;
XX
DR WPI; 2015-36079U/44.
XX
CC PT Recombinantly producing a soluble polypeptide comprises transfecting a
CC PT eukaryotic cell with a nucleic acid encoding the modified polypeptide
CC PT comprising the artificial glycosylation sites.
XX
CC PS Example 6; SEQ ID NO 20; 83pp; English.
XX
CC The present invention relates to a novel method for recombinantly
CC producing a polypeptide in soluble form. The method comprises: (a)
CC transfecting an eukaryotic cell with a nucleic acid encoding the
CC polypeptide, whereby the polypeptide has been modified by introducing one
CC or more artificial glycosylation sites (preferably N-glycosylation sites)
CC ; (b) cultivating the transfected cell in a cultivation medium; and (c)
CC recovering the polypeptide from the cultivation medium. The polypeptide
CC is a fusion polypeptide comprising at least a first part and a second
CC part conjugated to each other by a peptide linker. The method of the
CC present invention is useful for recombinantly producing a polypeptide in
CC soluble form and for increasing the yield of the recombinantly produced
CC soluble monomeric polypeptide. The present sequence represents a human
CC wild-type pre-pro-BDNF protein which can be used for constructing the
CC fusion protein of the present invention.
XX
SQ Sequence 247 AA;
Query Match 100.0%; Score 655; DB 22; Length 247;
Best Local Similarity 100.0%;
Matches 128; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MTILFLTMVISYFGCMKAAPMKEANIRGQGGLAYPGVRTHGTLESVNGPKAGSRGLTSLA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MTILFLTMVISYFGCMKAAPMKEANIRGQGGLAYPGVRTHGTLESVNGPKAGSRGLTSLA 60
Qy 61 DTFEHVIEELLDEDQKVRPNEENNKDADLYTSRVMLSSQVPLEPPLLFLLEEYKNYLDAA 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 DTFEHVIEELLDEDQKVRPNEENNKDADLYTSRVMLSSQVPLEPPLLFLLEEYKNYLDAA 120
Qy 121 NMSMRVRR 128
||||||||
Db 121 NMSMRVRR 128
WO2015091144 teaches a BDNF comprising instant SEQ ID NO:1 (see the sequence alignment below).
SEQ ID NO:1
BCB31261
ID BCB31261 standard; protein; 247 AA.
XX
AC BCB31261;
XX
DT 13-AUG-2015 (first entry)
XX
DE Human wild-type pre-pro-BDNF protein, SEQ ID 20.
XX
KW BDNF protein; Brain derived neurotrophic factor ligand;
KW alzheimers disease; antidepressant; antiparkinsonian; autism;
KW brain disease; down syndrome; eating disorder; eating-disorders-gen.;
KW furin; genetic-disease-gen.; growth-disorder-gen.; huntingtons chorea;
KW immunosuppressive; major depressive disorder; motor neurone disease;
KW multiple sclerosis; neuroleptic; neuroprotective; nootropic;
KW parkinsons disease; protein production; protein therapy;
KW psychiatric-gen.; recombinant protein; rett syndrome; schizophrenia;
KW spinal cord injury; substrate; therapeutic; vulnerary.
XX
OS Homo sapiens.
XX
FH Key Location/Qualifiers
FT Cleavage-site 125..128
FT /note= "Furin cleavage site"
FT Protein 129..247
FT /label= Mature_BDNF_protein
XX
CC PN WO2015091144-A1.
XX
CC PD 25-JUN-2015.
XX
CC PF 10-DEC-2014; 2014WO-EP077196.
XX
PR 20-DEC-2013; 2013EP-00198738.
XX
CC PA (HOFF ) HOFFMANN LA ROCHE & CO AG F.
CC PA (HOFF ) HOFFMANN LA ROCHE INC.
XX
CC PI Kopetzki E, Niewoehner J, Maier P;
XX
DR WPI; 2015-36079N/46.
XX
CC PT Producing recombinant polypeptide, involves cultivating mammalian cell
CC PT comprising nucleic acid encoding polypeptide and recovering recombinant
CC PT variant polypeptide or variant pro-polypeptide from cell or cultivation
CC PT medium.
XX
CC PS Example 3; SEQ ID NO 20; 69pp; English.
XX
CC The present invention relates to a novel method for producing a
CC recombinant polypeptide using a variant pro-polypeptide. The method
CC involves comprises: (a) cultivating a mammalian cell comprising a nucleic
CC acid encoding the polypeptide as pro-polypeptide (fusion polypeptide of a
CC pro-segment and the polypeptide); and (b) recovering the recombinant
CC variant polypeptide or the variant pro-polypeptide from the cell or
CC cultivation medium, where the endogenous enzymatic cleavage site between
CC the pro-segment and the polypeptide is replaced by an exogenous protease
CC cleavage site. The fusion protein comprises: (a) a fusion-polypeptide
CC comprising a biologically active entity, a linker peptide, and a
CC monovalent binding entity which binds to a blood-brain-barrier (BBB)
CC receptor; (b) and a wild-type, variant or a fragment of a neurotrophic
CC factor polypeptide such as a nerve growth factor (NGF), a brain derived
CC neurotrophic factor (BDNF), a glial cell line-derived neurotrophic factor
CC (GDNF), a neurotrophin 3 (NT-3), and a neurotrophin 4. The BDNF protein
CC can be used for treating or alleviating the symptoms of Alzheimer's,
CC Parkinson's, Huntington's and perinatal white matter disease, Down and
CC autism/Rett syndrome, schizophrenia, depression, eating disorders,
CC amyotrophic lateral sclerosis, multiple sclerosis, neuronal injuries like
CC that of the spinal cord as well as other diseases. The method is useful
CC for improving the production of poorly expressed polypeptides. The method
CC produces recombinant polypeptide simply without impairing biophysical
CC and/or biochemical properties, and/or biological function of the
CC polypeptide, and exhibits reduced complexity during downstream
CC processing. The present sequence represents a human wild-type pre-pro-
CC BDNF protein, used in the method for producing the recombinant protein.
XX
SQ Sequence 247 AA;
Query Match 100.0%; Score 655; DB 22; Length 247;
Best Local Similarity 100.0%;
Matches 128; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MTILFLTMVISYFGCMKAAPMKEANIRGQGGLAYPGVRTHGTLESVNGPKAGSRGLTSLA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MTILFLTMVISYFGCMKAAPMKEANIRGQGGLAYPGVRTHGTLESVNGPKAGSRGLTSLA 60
Qy 61 DTFEHVIEELLDEDQKVRPNEENNKDADLYTSRVMLSSQVPLEPPLLFLLEEYKNYLDAA 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 DTFEHVIEELLDEDQKVRPNEENNKDADLYTSRVMLSSQVPLEPPLLFLLEEYKNYLDAA 120
Qy 121 NMSMRVRR 128
||||||||
Db 121 NMSMRVRR 128
WO2013138795 teaches a BDNF comprising instant SEQ ID NO:1 (see the sequence alignment below).
SEQ ID NO:1
BAT19772
ID BAT19772 standard; protein; 247 AA.
XX
AC BAT19772;
XX
DT 07-NOV-2013 (first entry)
XX
DE Human brain-derived neurotrophic factor isoform a preproprotein, SEQ 120.
XX
KW Brain derived neurotrophic factor ligand; drug delivery;
KW protein engineering; protein production.
XX
OS Homo sapiens.
XX
CC PN WO2013138795-A1.
XX
CC PD 19-SEP-2013.
XX
CC PF 15-MAR-2013; 2013WO-US032686.
XX
PR 15-MAR-2012; 2012US-0611493P.
XX
CC PA (PERM-) PERMEON BIOLOGICS INC.
XX
CC PI Dewitt A, Edwards J, Franzusoff A, Vogan EM;
XX
DR WPI; 2013-N55042/65.
XX
CC PT New fusion protein comprising Surf+ penetrating polypeptide and antibody
CC PT or antibody-mimic moiety that binds to intracellular target and inhibits
CC PT binding between target and another protein, useful for treating e.g.
CC PT autoimmune disorders.
XX
CC PS Disclosure; SEQ ID NO 120; 278pp; English.
XX
CC The present invention relates to a novel fusion protein comprising a surf
CC protein, a penetrating polypeptide and an antibody or antibody-mimic
CC (AAM) moiety. The protein has an improved binding, inhibitory, affinity
CC and specificity properties. The invention further provides: a nucleic
CC acid sequence encoding the fusion protein; a vector comprising the
CC nucleic acid sequence; a host cell comprising the vector; a method for
CC preparing the fusion protein; a method for inhibiting the activity of an
CC intracellular target in a cell; a composition comprising the fusion
CC protein and a pharmaceutically acceptable carrier; a method for
CC modulating the activity of the intracellular target in a cell; a method
CC for delivering the AAM moiety into a cell; and a method for inhibiting
CC Hif1-alpha activity, STAT-5 activity or ras activity in a cell. The
CC present sequence represents a human brain-derived neurotrophic factor
CC isoform a preproprotein, which is a penetrating polypeptide a part of the
CC fusion protein used for delivering the antibodies or AAM moiety.
XX
SQ Sequence 247 AA;
Query Match 100.0%; Score 655; DB 20; Length 247;
Best Local Similarity 100.0%;
Matches 128; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MTILFLTMVISYFGCMKAAPMKEANIRGQGGLAYPGVRTHGTLESVNGPKAGSRGLTSLA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MTILFLTMVISYFGCMKAAPMKEANIRGQGGLAYPGVRTHGTLESVNGPKAGSRGLTSLA 60
Qy 61 DTFEHVIEELLDEDQKVRPNEENNKDADLYTSRVMLSSQVPLEPPLLFLLEEYKNYLDAA 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 DTFEHVIEELLDEDQKVRPNEENNKDADLYTSRVMLSSQVPLEPPLLFLLEEYKNYLDAA 120
Qy 121 NMSMRVRR 128
||||||||
Db 121 NMSMRVRR 128
US2015299687 teaches a BDNF comprising instant SEQ ID NO:1 (see the sequence alignment below).
SEQ ID NO:1
BCG03776
ID BCG03776 standard; protein; 199 AA.
XX
AC BCG03776;
XX
DT 17-DEC-2015 (first entry)
XX
DE Human neurotrophic factor protein SEQ ID NO: 7.
XX
KW central nervous system disease; gene therapy; growth; neuroprotective;
KW neurotrophic factor; spinal cord injury; therapeutic; vulnerary.
XX
OS Homo sapiens.
XX
CC PN US2015299687-A1.
XX
CC PD 22-OCT-2015.
XX
CC PF 06-NOV-2014; 2014US-00535113.
XX
PR 02-AUG-2010; 2010US-00848564.
XX
CC PA (GRUS/) GRUSKIN E A.
CC PA (CAGG/) CAGGIANO A O.
CC PA (ROYG/) ROY G.
CC PA (IACI/) IACI J.
CC PA (ZIMB/) ZIMBER M P.
XX
CC PI Gruskin EA, Caggiano AO, Roy G, Iaci J, Zimber MP;
XX
DR WPI; 2015-64174H/75.
XX
CC PT Composition used for promoting recovery of neurological function
CC PT comprises a polypeptide comprising a protein transduction domain and a
CC PT proteoglycan degrading domain.
XX
CC PS Disclosure; SEQ ID NO 7; 178pp; English.
XX
CC The invention relates to novel fusion proteins for the treatment of
CC central nervous system (CNS). The invention claims: 1) a composition
CC which comprises a polypeptide comprising a protein transduction domain
CC and a proteoglycan degrading domain, where the proteoglycan degrading
CC domain is selected from the group consisting of chondroitinase ABC,
CC chondroitinase ABC II, hyaluronidase-1, hyaluronidase-2, hyaluronidase-3,
CC hyaluronidase-4, PH-20, chondroitinase B, chondroitinase AC, and a
CC combination; and 2) a method of promoting recovery of neurological
CC function. The composition is used for treating spinal cord injuries and
CC related disorders of the CNS, promoting regeneration of axons, and
CC promoting plasticity, regrowth, repair, and/or regeneration of
CC dysfunctional neurons in the CNS. The present sequence represents a human
CC neurotrophic factor protein which is used for the treatment of CNS.
XX
SQ Sequence 199 AA;
Query Match 100.0%; Score 655; DB 22; Length 199;
Best Local Similarity 100.0%;
Matches 128; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MTILFLTMVISYFGCMKAAPMKEANIRGQGGLAYPGVRTHGTLESVNGPKAGSRGLTSLA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MTILFLTMVISYFGCMKAAPMKEANIRGQGGLAYPGVRTHGTLESVNGPKAGSRGLTSLA 60
Qy 61 DTFEHVIEELLDEDQKVRPNEENNKDADLYTSRVMLSSQVPLEPPLLFLLEEYKNYLDAA 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 DTFEHVIEELLDEDQKVRPNEENNKDADLYTSRVMLSSQVPLEPPLLFLLEEYKNYLDAA 120
Qy 121 NMSMRVRR 128
||||||||
Db 121 NMSMRVRR 128
JP2011246420 teaches a BDNF comprising instant SEQ ID NO:1 (see the sequence alignment below).
SEQ ID NO:1
AZQ26164
ID AZQ26164 standard; protein; 128 AA.
XX
AC AZQ26164;
XX
DT 19-JAN-2012 (first entry)
XX
DE Human brain-derived neurotrophic factor (BDNF) protein, SEQ ID:3.
XX
KW BDNF protein; Brain derived neurotrophic factor ligand;
KW Brain-derived neurotrophic factor; brain disease; drug screening;
KW neuroprotective; prophylactic to disease; protein production;
KW protein therapy; therapeutic.
XX
OS Homo sapiens.
XX
FH Key Location/Qualifiers
FT Peptide 1..18
FT /note= "BDNF propeptide"
FT Protein 19..128
FT /note= "Mature human BDNF protein"
XX
CC PN JP2011246420-A.
XX
CC PD 08-DEC-2011.
XX
CC PF 31-MAY-2010; 2010JP-00123957.
XX
PR 31-MAY-2010; 2010JP-00123957.
XX
CC PA (NIIT ) DOKURITSU GYOSEI HOJIN SANGYO GIJUTSU SO.
XX
CC PI Hara T, Kojima M, Uegaki K, Mizui T, Kumanogo H, Ishikawa Y;
XX
DR WPI; 2011-P88680/81.
XX
CC PT Use of propeptide cleaved from growth factor precursor as bioactive
CC PT substance for mature-type growth factor e.g. brain derived neurotrophic
CC PT factor for preventing or treating brain disease.
XX
CC PS Example 1; SEQ ID NO 3; 20pp; Japanese.
XX
CC The present invention relates to the novel use of a propeptide cleaved
CC from growth factor precursor as bioactive substance for mature-type
CC growth factor. The propeptide has a firm bonding with the mature-type
CC growth factor even after it is cleaved from the growth factor precursor.
CC The invention provides a method of production of the propeptide. The
CC propeptide is useful as bioactive substance for controlling at least one
CC bioactivity of mature-type growth factor, preferably brain-derived
CC neurotrophic factor (BDNF) by inhibiting the growth factor. The invention
CC provides a method for screening medicines for inhibiting the propeptide.
CC The method involves allowing the propeptide to act on a cell in vivo or
CC in vitro, and then allowing the target compound to act on the cell. The
CC propeptide is useful for the screening of medicines including
CC antidepressants that are used for preventing or treating brain disorders.
CC The present sequence corresponds to the human brain-derived neurotrophic
CC factor (BDNF) protein which is used to produce the brain-derived
CC neurotrophic factor (BDNF) propeptide which is used for screening of
CC medicines including antidepressants that are used for preventing or
CC treating brain disorders.
XX
SQ Sequence 128 AA;
Query Match 100.0%; Score 655; DB 18; Length 128;
Best Local Similarity 100.0%;
Matches 128; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MTILFLTMVISYFGCMKAAPMKEANIRGQGGLAYPGVRTHGTLESVNGPKAGSRGLTSLA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MTILFLTMVISYFGCMKAAPMKEANIRGQGGLAYPGVRTHGTLESVNGPKAGSRGLTSLA 60
Qy 61 DTFEHVIEELLDEDQKVRPNEENNKDADLYTSRVMLSSQVPLEPPLLFLLEEYKNYLDAA 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 DTFEHVIEELLDEDQKVRPNEENNKDADLYTSRVMLSSQVPLEPPLLFLLEEYKNYLDAA 120
Qy 121 NMSMRVRR 128
||||||||
Db 121 NMSMRVRR 128
JP2015083015 teaches a BDNF comprising instant SEQ ID NO:1 (see the sequence alignment below).
SEQ ID NO:1
BBZ06342
ID BBZ06342 standard; protein; 128 AA.
XX
AC BBZ06342;
XX
DT 18-JUN-2015 (first entry)
XX
DE Human brain-derived neurotrophic factor (BDNF), SEQ ID 3.
XX
KW BDNF protein; Brain derived neurotrophic factor ligand;
KW Brain-derived neurotrophic factor; antidepressant; biomarker;
KW brain disease; drug screening; neuroprotective; prophylactic to disease;
KW protein inhibition; therapeutic.
XX
OS Homo sapiens.
OS Synthetic.
XX
FH Key Location/Qualifiers
FT Region 19..128
FT /label= Pro_peptide
FT /note= "Human brain-derived neurotrophic factor (BDNF)
FT propeptide"
XX
CC PN JP2015083015-A.
XX
CC PD 30-APR-2015.
XX
CC PF 05-JAN-2015; 2015JP-00000124.
XX
PR 31-MAY-2010; 2010JP-00123957.
XX
CC PA (NIIT ) DOKURITSU GYOSEI HOJIN SANGYO GIJUTSU SO.
XX
CC PI Kojima M, Uegaki K, Mizui T, Kumanogo H, Ishikawa Y, Hara T;
XX
DR WPI; 2015-27122S/31.
DR GENBANK; CAA62632.
XX
CC PT Screening method of medicinal substance which inhibits action of brain-
CC PT derived neurotrophic factor (BDNF) propeptide useful for preventing or
CC PT treating brain disease, by making propeptide and candidate compound of
CC PT BDNF to act on cell.
XX
CC PS Disclosure; SEQ ID NO 3; 14pp; Japanese.
XX
CC The present invention relates to a novel method for screening a drug
CC substance capable of inhibiting the action of a brain-derived
CC neurotrophic factor (BDNF) propeptide. Also described is a biomarker
CC comprising the BDNF propeptide. The method of the present invention is
CC useful for screening a drug substance (preferably an antidepressant or a
CC long-term depression (LTD) inhibitor) useful for preventing and treating
CC brain disease and for increasing number of GluR1 cluster. The present
CC sequence represents a human BDNF protein, whose propeptide (19-128) can
CC be used in the method of the present invention for screening a drug
CC substance for preventing and treating brain disease.
XX
SQ Sequence 128 AA;
Query Match 100.0%; Score 655; DB 22; Length 128;
Best Local Similarity 100.0%;
Matches 128; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MTILFLTMVISYFGCMKAAPMKEANIRGQGGLAYPGVRTHGTLESVNGPKAGSRGLTSLA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MTILFLTMVISYFGCMKAAPMKEANIRGQGGLAYPGVRTHGTLESVNGPKAGSRGLTSLA 60
Qy 61 DTFEHVIEELLDEDQKVRPNEENNKDADLYTSRVMLSSQVPLEPPLLFLLEEYKNYLDAA 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 DTFEHVIEELLDEDQKVRPNEENNKDADLYTSRVMLSSQVPLEPPLLFLLEEYKNYLDAA 120
Qy 121 NMSMRVRR 128
||||||||
Db 121 NMSMRVRR 128
JP2016193899 teaches a BDNF comprising instant SEQ ID NO:1 (see the sequence alignment below).
SEQ ID NO:1
BDJ33840
ID BDJ33840 standard; protein; 247 AA.
XX
AC BDJ33840;
XX
DT 29-DEC-2016 (first entry)
XX
DE Human brain-derived neurotrophic factor (proBDNF) propeptide, SEQ ID 1.
XX
KW BDNF protein; Brain derived neurotrophic factor ligand; brain disease;
KW diagnostic test; immuno-diagnosis.
XX
OS Homo sapiens.
XX
FH Key Location/Qualifiers
FT Peptide 1..18
FT /label= Signal_peptide
FT Protein 19..247
FT /note= "Mature BDNF"
FT Protein 19..128
FT /note= "Specifically claimed in claim 1"
XX
CC PN JP2016193899-A.
XX
CC PD 17-NOV-2016.
XX
CC PF 01-APR-2016; 2016JP-00074191.
XX
PR 01-APR-2015; 2015JP-00075401.
XX
CC PA (NIIT ) DOKURITSU GYOSEI HOJIN SANGYO GIJUTSU SO.
XX
CC PI Kojima M, Uegaki K, Mizui T, Kumanogo H, Hara T;
XX
DR WPI; 2016-70699L/79.
DR GENBANK; CAA62632.
XX
CC PT New antibody capable of recognizing brain-derived neurotrophic factor
CC PT (BDNF) prodomain and BDNF propeptide of proBDNF and specific regions of
CC PT BDNF prodomain, useful e.g. for analyzing histochemically nerve
CC PT pathological condition.
XX
CC PS Claim 1; SEQ ID NO 1; 14pp; Japanese.
XX
CC The present invention relates to a novel antibody capable of recognizing
CC brain-derived neurotrophic factor (BDNF) prodomain. The antibody is
CC useful for diagnosing nerve pathological conditions or brain disorders
CC resulting from proBDNF or BDNF propeptide. The present sequence is a
CC human brain-derived neurotrophic factor (proBDNF) propeptide, useful for
CC preparing the antibody for diagnosing brain disorders. Note: A fragment
CC of the present sequence corresponding to residues 19-128 (see BDJ33846)
CC is specifically claimed in Claim 1.
XX
SQ Sequence 247 AA;
Query Match 100.0%; Score 655; DB 23; Length 247;
Best Local Similarity 100.0%;
Matches 128; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MTILFLTMVISYFGCMKAAPMKEANIRGQGGLAYPGVRTHGTLESVNGPKAGSRGLTSLA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MTILFLTMVISYFGCMKAAPMKEANIRGQGGLAYPGVRTHGTLESVNGPKAGSRGLTSLA 60
Qy 61 DTFEHVIEELLDEDQKVRPNEENNKDADLYTSRVMLSSQVPLEPPLLFLLEEYKNYLDAA 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 DTFEHVIEELLDEDQKVRPNEENNKDADLYTSRVMLSSQVPLEPPLLFLLEEYKNYLDAA 120
Qy 121 NMSMRVRR 128
||||||||
Db 121 NMSMRVRR 128
CN101245351 teaches a BDNF comprising instant SEQ ID NO:1 (see the sequence alignment below).
SEQ ID NO:2
ATS13262
ID ATS13262 standard; protein; 241 AA.
XX
AC ATS13262;
XX
DT 05-FEB-2009 (first entry)
XX
DE Human nerve growth factor (NGF-beta), SEQ ID 4.
XX
KW protein production; therapeutic; protein therapy; nerve growth factor;
KW nerve growth factor-beta; BOND_PC; nerve growth factor, beta polypeptide;
KW Nerve growth factor, beta; NGFB; NGF; HSAN5;
KW nerve growth factor, beta subunit; beta-nerve growth factor; Beta-NGF;
KW nerve growth factor, beta polypeptide precursor; MGC161426; MGC161428;
KW nerve growth factor B; nerve growth factor beta polypeptide; GO5057;
KW GO7267; GO7275; GO7422; GO8083; GO19233; GO45664.
XX
OS Homo sapiens.
XX
CC PN CN101245351-A.
XX
CC PD 20-AUG-2008.
XX
CC PF 14-DEC-2007; 2007CN-10199227.
XX
PR 14-DEC-2007; 2007CN-10199227.
XX
CC PA (UYNW-) UNIV NORTHWEST AGRIC & FOREST SCI & TECH.
XX
CC PI Li Q, Xiao B, Han Z, Hu J;
XX
DR WPI; 2009-A98378/06.
DR PC:NCBI; gi70995319.
DR PC:SWISSPROT; P01138.
XX
CC PT Preparing active protein as medicament for treating, comprises
CC PT constructing target and modifier protein gene into lower stream of
CC PT promoter in shuttle vector and combining expression cassette containing
CC PT gene into adenovirus gene frame.
XX
CC PS Example 2; SEQ ID NO 4; 21pp; Chinese.
XX
CC The present invention relates to a method for producing an active protein
CC in vitro. The method of the invention comprises: (i) introducing a target
CC protein gene and a modifier protein gene into the downstream region of a
CC promoter in a shuttle vector for producing the fusion gene, (ii) using
CC molecular recombination to introduce the expression cassette containing
CC the gene into an adenovirus gene frame, to construct a recombinant
CC replication-deficit adenovirus carrier, (iii) modifying the adenovirus
CC carrier by a helper cell, and introducing the adenovirus carrier
CC containing the fusion gene into animal breast, (iv) obtaining the active
CC protein from the breast milk secreted from the animal breast epithelial
CC cell. The target protein gene is selected from human protein C in serine
CC lytic cell protein, nerve growth factor, insulin, insulin-like growth
CC factor, insulin pre-receptor, transforming growth factor beta 1,
CC parathyroid gland hormone related protein, blood coagulation factor,
CC pancreatic protease, trypsin, elastase, plasmin, Clr and Cls. The
CC modifier protein gene is selected from human furin in serine lytic cell
CC protein, yeast Kex2 endopeptidase, subtilisin. The shuttle vector is
CC selected from the pShuttle, pShuttle-cmv, pDC311 and pDD315. The
CC adenovirus frame carrier is selected from: pAdeasy, pBHGlox and El.3Cre.
CC The active protein produced using the method of the invention can be used
CC for the treatment of diseases. The present sequence is the amino acid
CC sequence of human nerve growth factor-beta (NGF-beta) used as a target
CC protein in a method of the invention.
CC
CC Revised record issued on 17-NOV-2008 : Enhanced with precomputed
CC information from BOND.
XX
SQ Sequence 241 AA;
Query Match 100.0%; Score 619; DB 14; Length 241;
Best Local Similarity 100.0%;
Matches 121; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MSMLFYTLITAFLIGIQAEPHSESNVPAGHTIPQAHWTKLQHSLDTALRRARSAPAAAIA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MSMLFYTLITAFLIGIQAEPHSESNVPAGHTIPQAHWTKLQHSLDTALRRARSAPAAAIA 60
Qy 61 ARVAGQTRNITVDPRLFKKRRLRSPRVLFSTQPPREAADTQDLDFEVGGAAPFNRTHRSK 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ARVAGQTRNITVDPRLFKKRRLRSPRVLFSTQPPREAADTQDLDFEVGGAAPFNRTHRSK 120
Qy 121 R 121
|
Db 121 R 121
US2010303811 teaches an immunostimulatory fusion protein production related protein comprising instant SEQ ID NO:2 (see the sequence alignment below).
SEQ ID NO:2
AYM52834
ID AYM52834 standard; protein; 241 AA.
XX
AC AYM52834;
XX
DT 03-FEB-2011 (first entry)
XX
DE Immunostimulatory fusion protein production related protein, SEQ ID 36.
XX
KW allergy; antiallergic; antiinflammatory; antimicrobial-gen.;
KW autoimmune disease; cancer; cytostatic; immune inhibition;
KW immune stimulation; immunity; immunosuppressive; infection;
KW inflammatory disease; prophylactic to disease; protein production;
KW protein therapy; recombinant protein; therapeutic; transplant rejection;
KW vaccine, antiviral; viral infection; virucide; BOND_PC;
KW nerve growth factor, beta polypeptide; Nerve growth factor, beta; NGFB;
KW NGF; HSAN5; nerve growth factor, beta subunit; beta-nerve growth factor;
KW Beta-NGF; nerve growth factor, beta polypeptide precursor; MGC161426;
KW MGC161428; nerve growth factor B; nerve growth factor beta polypeptide;
KW GO5057; GO7267; GO7275; GO7422; GO8083; GO19233; GO45664.
XX
OS Homo sapiens.
XX
FH Key Location/Qualifiers
FT Peptide 1..17
FT /label= Signal_peptide
FT Protein 18..241
FT /note= "Mature immunostimulatory fusion protein
FT production related protein"
XX
CC PN US2010303811-A1.
XX
CC PD 02-DEC-2010.
XX
CC PF 12-JUN-2009; 2009US-00483876.
XX
PR 16-JUN-2008; 2008US-0073010P.
XX
CC PA (OCHI/) OCHI A.
XX
CC PI Ochi A;
XX
DR WPI; 2010-P97199/82.
DR N-PSDB; AYM52833.
DR PC:NCBI; gi70995319.
DR PC:SWISSPROT; P01138.
XX
CC PT Generating recombinant fusion polypeptides comprising two different
CC PT receptor-ligand-binding domains e.g. TNF family receptor and ligands,
CC PT useful for eliciting or suppressing specific immune response in e.g.
CC PT cancer and allergy patients.
XX
CC PS Disclosure; SEQ ID NO 36; 114pp; English.
XX
CC The present invention relates to a method for producing recombinant
CC immunostimulatory fusion polypeptides comprising two different receptor-
CC ligand-binding domains (e.g. (i) TNF family receptor and ligands, (ii)
CC immunoglobulin super family co-stimulatory receptors and ligands and
CC (iii) cytokines and third polypeptide domain in N-terminal to C-terminal.
CC The invention provides: (1) a recombinant nucleic acid (cDNA) comprising
CC a polynucleotide sequence encoding a fusion polypeptide; (2) a cDNA
CC expression vector containing the fusion polynucleotide sequence; (3) a
CC cell line producing the fusion protein; and (4) a method for eliciting or
CC suppressing an antigen specific immune response in a subject, involves
CC administering the fusion polypeptide or the expression vector and an
CC antigen (optional) correlated to a specific disease. The recombinant
CC immunostimulatory fusion polypeptides are useful for preventing, treating
CC by eliciting or suppressing antigen specific immune response in a subject
CC suffering from diseases chosen from cancers, allergies, autoimmune
CC diseases, infectious diseases and inflammatory conditions. The fusion
CC proteins are used as immune adjuvants and vaccines for treating various
CC chronic diseases such as viral infection and as immune suppressant for
CC treating various chronic diseases, such as autoimmunity and organ
CC transplant rejection. The present sequence is a recombinant
CC immunostimulatory fusion protein production related protein, used in the
CC invention.
CC
CC Revised record issued on 18-JAN-2011 : Enhanced with precomputed
CC information from BOND.
XX
SQ Sequence 241 AA;
Query Match 100.0%; Score 619; DB 17; Length 241;
Best Local Similarity 100.0%;
Matches 121; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MSMLFYTLITAFLIGIQAEPHSESNVPAGHTIPQAHWTKLQHSLDTALRRARSAPAAAIA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MSMLFYTLITAFLIGIQAEPHSESNVPAGHTIPQAHWTKLQHSLDTALRRARSAPAAAIA 60
Qy 61 ARVAGQTRNITVDPRLFKKRRLRSPRVLFSTQPPREAADTQDLDFEVGGAAPFNRTHRSK 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ARVAGQTRNITVDPRLFKKRRLRSPRVLFSTQPPREAADTQDLDFEVGGAAPFNRTHRSK 120
Qy 121 R 121
|
Db 121 R 121
US2014200261 teaches an oncology related target protein NGF comprising instant SEQ ID NO:2 (see the sequence alignment below).
SEQ ID NO:2
BBK45912
ID BBK45912 standard; protein; 241 AA.
XX
AC BBK45912;
XX
DT 11-SEP-2014 (first entry)
XX
DE Oncology related target protein NGF, SEQ ID 1791.
XX
KW abnormal leukocyte count; analgesic; anticoagulant; antimicrobial-gen.;
KW antipruritic; antipyretic; antitussive; apoptosis stimulation;
KW bladder disease; cancer; cell growth; cough; cytostatic; dermatological;
KW dizziness; dyspnea; fatigue; fever; gastrointestinal-gen.; gene therapy;
KW headache; hematological-gen.; hemorrhage; hemostatic; hepatotropic;
KW hoarseness; hypercalcemia; hyperpigmentation; indigestion;
KW intestine disease; jaundice; metabolic-gen.; neuroprotective; nevus;
KW nutrition-disorder-gen.; otorhinolaryngological-gen.; pain;
KW prophylactic to disease; protein therapy; pruritus; respiratory-gen.;
KW therapeutic; thrombolytic; thrombosis; uropathic; verruca vulgaris;
KW virucide; weight loss.
XX
OS Homo sapiens.
XX
CC PN US2014200261-A1.
XX
CC PD 17-JUL-2014.
XX
CC PF 30-SEP-2013; 2013US-00041011.
XX
PR 17-JAN-2013; 2013US-0753661P.
PR 18-JAN-2013; 2013US-0754159P.
PR 14-MAR-2013; 2013US-0781097P.
PR 31-MAY-2013; 2013US-0829334P.
PR 27-JUN-2013; 2013US-0839893P.
PR 03-JUL-2013; 2013US-0842733P.
PR 23-JUL-2013; 2013US-0857304P.
XX
CC PA (MODE-) MODERNA THERAPEUTICS INC.
XX
CC PI Hoge SG, Chakraborty T, Frederick JP, John M, De Fougerolles A;
XX
DR WPI; 2014-N47918/51.
DR N-PSDB; BBK44752.
XX
CC PT New isolated synthetic signal-sensor polynucleotide useful for e.g.
CC PT treating disease, disorder and/or condition e.g. adrenal cortical cancer,
CC PT and aplastic anemia in e.g. human, contains mRNA encoding oncology-
CC PT related polypeptide.
XX
CC PS Disclosure; SEQ ID NO 1791; 334pp; English.
XX
CC The present invention relates to a novel isolated synthetic signal-sensor
CC polynucleotide comprising an mRNA encoding oncology-related polypeptide
CC of interest and one or more sensor sequences. The synthetic signal-sensor
CC polynucleotide is useful for increasing the level of the oncology-related
CC polypeptide of interest for: treating a disease, disorder and/or
CC condition in a subject, where the disease, disorder and/or condition is a
CC cancer; reducing, eliminating or preventing tumor growth in a subject;
CC reducing and/or ameliorating at least one symptom of cancer in a subject,
CC where the symptom is chosen from weakness, aches and pains, fever,
CC fatigue, weight loss, blood clots, increased blood calcium levels, low
CC white blood cell count, short of breath, dizziness, headaches,
CC hyperpigmentation, jaundice, erthema, pruritis, excessive hair growth,
CC change in bowel habits, change in bladder function, long-lasting sores,
CC white patches inside the mouth, white spots on the tongue, unusual
CC bleeding or discharge, thickening or lump on parts of the body,
CC indigestion, trouble swallowing, changes in warts or moles, change in new
CC skin and nagging cough and hoarseness; and preferentially inducing cell
CC death in cancer cells in a tissue or organ. Sequences BBK45442-BBK46608
CC are oncology related target proteins which are used for treating a cancer
CC or its symptoms in a subject.
XX
SQ Sequence 241 AA;
Query Match 100.0%; Score 619; DB 21; Length 241;
Best Local Similarity 100.0%;
Matches 121; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MSMLFYTLITAFLIGIQAEPHSESNVPAGHTIPQAHWTKLQHSLDTALRRARSAPAAAIA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MSMLFYTLITAFLIGIQAEPHSESNVPAGHTIPQAHWTKLQHSLDTALRRARSAPAAAIA 60
Qy 61 ARVAGQTRNITVDPRLFKKRRLRSPRVLFSTQPPREAADTQDLDFEVGGAAPFNRTHRSK 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ARVAGQTRNITVDPRLFKKRRLRSPRVLFSTQPPREAADTQDLDFEVGGAAPFNRTHRSK 120
Qy 121 R 121
|
Db 121 R 121
US2014206852 teaches a human oncology related target protein NGF comprising instant SEQ ID NO:2 (see the sequence alignment below).
SEQ ID NO:2
BBK83237
ID BBK83237 standard; protein; 241 AA.
XX
AC BBK83237;
XX
DT 11-SEP-2014 (first entry)
XX
DE Human oncology related target protein NGF, SEQ 1791.
XX
KW NGF; adrenal cortical carcinoma; anal tumor; antianemic; aplastic anemia;
KW bladder cancer; bone metastases; bone tumor; brain tumor; breast tumor;
KW cytostatic; endocrine-gen.; gastrointestinal-gen.; gynecological;
KW hematological-gen.; metastasis; musculoskeletal-gen.;
KW nerve growth factor (beta polypeptide); neuroprotective; osteopathic;
KW prophylactic to disease; therapeutic; uropathic.
XX
OS Homo sapiens.
XX
CC PN US2014206852-A1.
XX
CC PD 24-JUL-2014.
XX
CC PF 20-DEC-2013; 2013US-00135876.
XX
PR 18-JAN-2013; 2013US-0754159P.
PR 14-MAR-2013; 2013US-0781097P.
PR 31-MAY-2013; 2013US-0829334P.
PR 27-JUN-2013; 2013US-0839893P.
PR 03-JUL-2013; 2013US-0842733P.
PR 23-JUL-2013; 2013US-0857304P.
PR 30-SEP-2013; 2013US-00041011.
XX
CC PA (MODE-) MODERNA THERAPEUTICS INC.
XX
CC PI Hoge SG, De Fougerolles A, Chakraborty T;
XX
DR WPI; 2014-N62698/52.
DR N-PSDB; BBK82077.
XX
CC PT New isolated synthetic signal-sensor polynucleotide useful for preventing
CC PT and/or treating disease, disorder and/or condition e.g. adrenal cortical
CC PT cancer, and advanced cancer, comprises mRNA.
XX
CC PS Disclosure; SEQ ID NO 1791; 332pp; English.
XX
CC The present invention relates to a novel isolated synthetic signal-sensor
CC polynucleotide comprising an mRNA which encodes an oncology-related
CC polypeptide of interest and a sensor sequence comprising SEQ ID NO: 3741
CC (see BBK85187). The signal-sensor polynucleotide is useful for preventing
CC and/or treating disease, disorder and/or condition such as adrenal
CC cortical cancer, advanced cancer, anal cancer, aplastic anemia, bile-duct
CC cancer, bladder cancer, bone cancer, brain cancer, and breast cancer. The
CC present sequence is a human oncology related target protein NGF involved
CC in apoptotic signaling (AS), useful for designing the synthetic signal-
CC sensor polynucleotide of the invention.
XX
SQ Sequence 241 AA;
Query Match 100.0%; Score 619; DB 21; Length 241;
Best Local Similarity 100.0%;
Matches 121; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MSMLFYTLITAFLIGIQAEPHSESNVPAGHTIPQAHWTKLQHSLDTALRRARSAPAAAIA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MSMLFYTLITAFLIGIQAEPHSESNVPAGHTIPQAHWTKLQHSLDTALRRARSAPAAAIA 60
Qy 61 ARVAGQTRNITVDPRLFKKRRLRSPRVLFSTQPPREAADTQDLDFEVGGAAPFNRTHRSK 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ARVAGQTRNITVDPRLFKKRRLRSPRVLFSTQPPREAADTQDLDFEVGGAAPFNRTHRSK 120
Qy 121 R 121
|
Db 121 R 121
15. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHANG-YU WANG whose telephone number is (571)272-4521. The examiner can normally be reached Monday-Thursday, 7:00am-5:00pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Stucker can be reached at 571-272-0911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
Chang-Yu Wang
July 14, 2026
/CHANG-YU WANG/Primary Examiner, Art Unit 1675
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