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
RESPONSE TO AMENDMENT
Status of Application/Amendments/claims
2. Applicant’s amendment filed July 22, 2026 is acknowledged. Claims 2, 4 and 13-19 are cancelled. Claims 1 and 11 are amended. Claims 1, 3 and 5-12 are pending in this application. Claims 5-10 are withdrawn without traverse (filed 05/06/2024) from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on May 6, 2024.
3. Claims 1, 3 and 11-12 are under examination in this office action.
4. Applicant’s arguments filed on July 22, 2026 have been fully considered but they are not deemed to be persuasive for the reasons set forth below.
Claim Rejections/Objections Maintained
In view of the amendment filed on July 22, 2026, the following rejections are maintained.
Claim Objections
5. Claims 1 and 11 are objected to because of the following informalities: the limitation “GFAP-a” recited in lines 7-8 of claims 1 and 11 is not consistent with the limitations “GFAPalpha” and “GFAPa” recited in lines 11-13 of claims 1 and 11. Appropriate correction is required.
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, 3 and 11-12 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. The rejection is maintained for the reasons of record and the reasons set forth below.
Briefly, claims 1, 3 and 11-12 are indefinite because the limitations “…with a residue range 1-72 in GFAP-a”, “…. with a residue range 378-432 in GFAP-a”, “…with a residue range 79-383 in GFAPa” and “GFAPalpha residue 1-432” recited in claims 1 and 11 are not clear. It is not clear whether the limitation “with a residue range 1-72 in GFAP-a” means “1-72 amino acid residues in length in GFAP-a” or “amino acids 1-72 at positions 1-72 of the sequence of a specific s GFAP-a". The same issue applies to the limitations ““…. with residue range 378-432 in GFAP-a”, “…with a residue range 79-383 in GFAPa” and “GFAPalpha residue 1-432” recited in claims 1 and 11. The term “improving cognitive function” recited in claim 11 is a relative term which renders the claim indefinite. The term “improving cognitive function” 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. It is not known on what standard, criteria or condition the “improving cognitive function”” is based on or relative to. The metes and bounds within the definition of the “improving cognitive function” are unknown and thus, a skilled artisan cannot envision what would be considered as “improving cognitive function” recited in the claim. Thus, the claim is indefinite. The rest of claims are indefinite as depending from an indefinite claim.
Response to Arguments
On p. 5 of the response, Applicant argues that the rejection has been overcome in view of amendment to claims 1 and 11 by deleting “about and “statistically significantly”.
Applicant's arguments have been fully considered but they are not found persuasive. Contrary to Applicant' s arguments, the examiner asserts that based on MPEP§2171-MPEP§2173, claims 1, 3 and 11-12 are indefinite because:
i. It is unclear whether the limitation “with a residue range about 1-72 in GFAP-a” means the amino acid number in length or the amino acid positions corresponding to a specific sequence. It is unclear whether the limitation “with a residue range about 1-72 in GFAP-a” means “at amino acid positions 1-72 of the sequence of a specific GFAP-a" or “1-72 amino acid residues in length in GFAP-a”. Further, If the limitation “with a residue range 1-72 in GFAP-a” means “at amino acid positions 1-72 of the sequence of a specific GFAP-a", it is still unclear whether the positions 1-72 in different isoforms of GFAP-a having different sequences with different lengths are the same amino acid residues or different. Since the metes and bounds of what is encompassed within the limitation “with a residue range 1-72 in GFAP-a” recited in claims 1 and 11 cannot be determined, a skilled artisan cannot envision what is included and within the scope of the claims. The same issue applies to the limitations “ with a residue range 378-432 in GFAP-a”, “GFAPalpha residues 1-432”, “with a residue range 79-383 in GFAPa”, “with a residue range 1-72 in GFAPa” and “with a residue range about 378-432 in GFAPa” recited in claims 1 and 11. Thus, the claims are indefinite.
ii. The term “improving cognitive function” recited in claim 11 is a relative term which renders the claim indefinite. The term “improving cognitive function” 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. It is not known on what standard, criteria or condition the “improving cognitive function”” is based on or relative to. The metes and bounds within the definition of the “improving cognitive function” are unknown and thus, a skilled artisan cannot envision what would be considered as “improving cognitive function” recited in the claim. Thus, the claim is indefinite.
iii. The rest of claims are indefinite as depending from an indefinite claim.
Accordingly, the rejection of claims 1, 3 and 11-12 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is maintained.
Claim Rejections - 35 USC § 112
7. 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, 3 and 11-12 stand rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. The rejection is maintained for the reasons of record and the reasons set forth below.
Claims 1, 3 and 11-12 as amended are drawn to methods for suppressing astrogliosis and improving cognitive function in a human subject in need thereof suffering from a neuroinjury, the method comprising:
i) administering to the subject an amount of GFAP or breakdown product thereof to achieve active immunization, or
ii) administering to the subject an anti-GFAP IgG or IgM antibody or GFAP-binding aptamer to suppress astrogliosis or achieve passive immunization;
wherein the GFAP breakdown product (GBDP) is selected from at least one of a central core GBDP of 38KDa, an N-terminal head region with a residue range 1-72 in GFAP-a and a C-terminal tail region with a residue range 378-432 in GFAP-a, and wherein the anti-GFAP antibody or aptamer binds to an antigen selected from the group consisting of a full-length GFAP isoform, a GFAP-a residue 1-432, a central core GFAP breakdown product with a residue range 79-383 in GFAPa, an N-terminal head region of GFAPa with a residue range 1-72 in GFAPa, and a C-terminal tail region of GFAPa with a residue range 378-432 in GFAPa, and wherein the neuroinjury optionally comprises or is selected from the group consisting of traumatic brain injury, stroke, spinal cord injury, cerebral hemorrhage, chronic and traumatic encephalopathy.
Briefly, claims 1, 3 and 11-12 as amended encompass using a structurally and functionally undefined GFAP, or a structurally and functionally undefined central core GFAP breakdown product (GBDP) of 38KDa, a structurally and functionally undefined N-terminal head region with a residue range 1-72 in GFAP-a or a structurally and functionally undefined C-terminal tail region with a residue range 378-432 in GFAP-a to achieve active immunization for suppressing astrogliosis or improving cognitive function in a human subject suffering from a neuroinjury. Claims 1, 3 and 11-12 as amended also encompass using a structurally and functionally undefined anti-GFAP IgG or IgM antibody or a structurally and functionally undefined GFAP-binding aptamer binding to an antigen selected from the group consisting of a full-length GFAP isoform, a GFAP-a residue 1-432, a central core GFAP breakdown product with a residue range 79-383 in GFAPa, an N-terminal head region of GFAPa with a residue range 1-72 in GFAPa, and a C-terminal tail region of GFAPa with a residue range 378-432 in GFAPa to achieve passive immunization for suppressing astrogliosis or improving cognitive function in a human subject suffering from a neuroinjury.
The specification provides no well-established structural and functional relationship or correlation between the intact full length wild type GFAP protein used in examples and the claimed GFAP or the claimed central core GFAP breakdown product (GBDP) of 38KDa, the claimed N-terminal head region with a residue range 1-72 in GFAP-a or the claimed C-terminal tail region with a residue range 378-432 in GFAP-a in suppressing astrogliosis or cognitive function in a human subject suffering from all forms of neuroinjury. The specification provides no well-established structural and functional relationship or correlation between immunization with the claimed GFAP or the claimed central core GFAP breakdown product (GBDP) of 38KDa, the claimed N-terminal head region with a residue range 1-72 in GFAP-a or the claimed C-terminal tail region with a residue range 378-432 in GFAP-a to achieve active immunization in suppressing astrogliosis or cognitive function in a human subject suffering from all forms of neuroinjury and reducing elevated GFAP levels induced by brain injury at days 20 but not levels of pNF-H or NSE (Examples 4-5, Figures 5A-B) based on preimmunization with the full-length GFAP in an animal at 6-8 weeks, and followed by cortical control impact surgeries at 10-12 weeks as an animal model of traumatic brain injury (TBI) shown in Examples 3-8. Thus, a skilled artisan cannot contemplate how to make and use the claimed invention, indicating undue experimentation is required by the skilled artisan to perform while practicing the claimed invention.
The specification provides no well-established structural and functional relationship or correlation between the defined mouse monoclonal anti-GFAP antibody cocktail (clones 1B4, 4A11, 2E1 from BD pharmigen) used in Examples 10-14 in reducing expression of GFAP and GBDP levels and the claimed anti-GFAP IgG or IgM antibody or GFAP-binding aptamer that binds to an antigen selected from the group consisting of a full-length GFAP isoform, a GFAP-a residue 1-432, a central core GFAP breakdown product with a residue range 79-383 in GFAPa, an N-terminal head region of GFAPa with a residue range 1-72 in GFAPa, and a C-terminal tail region of GFAPa with a residue range 378-432 in GFAPa in suppressing astrogliosis or cognitive function in a human subject suffering from all forms of neuroinjury . Thus, a skilled artisan cannot contemplate how to make and use the claimed invention, indicating that undue experimentation is required by the skilled artisan to perform while practicing the claimed invention.
The specification also provides no well-established structural and functional correlation between all forms of neuroinjury and an animal model of traumatic brain injury (TBI) shown in Examples 3-8 or Examples 10-14. Thus, it is unpredictable whether administration of the claimed GFAP breakdown product or the claimed anti-GFPA antibody or aptamer thereof can treat all forms of neuroinjury including traumatic brain injury, stroke, spinal cord injury, cerebral hemorrhage and chronic and traumatic encephalopathy recited in instant claims, indicating that undue experimentation is required by the skilled artisan to perform while practicing the claimed invention.
Therefore, in view of the breadth of the claims, the lack of guidance in the specification, the limited examples, the unpredictability of inventions, and the current status of the art, undue experimentation would be required by a skilled artisan to perform in order to practice the full scope of the claimed invention as it pertains to a method for suppressing astrogliosis or improving cognitive function in a human subject suffering from a neuroinjury by administering the claimed GFAP or the claimed GFAP breakdown products or the claimed anti-GFAP IgG or IgM or GFAP-binding aptamer binding to recited antigens to the human subject.
Response to Arguments
On p. 5-7 of the response, Applicant argues that i) the sequence ranges and fragments of GBDPs are known in the art and cites Zhang et al. (PloS One, 2014; 9:e92698), which is cited on p. 42 of the instant specification. ii) the instant specification provides support that both full length GFAP and GBDP-38KD are toxic to primary rat cerebrocortical neurons using an MTT mitochondrial assay as shown in Figure 11 and administering anti-GFAP therapy reduces the expression of GFAP and GBDP levels in ipsilateral cortex and hippocampus as shown in Figures 15A-B.
Applicant's arguments have been fully considered but they are not found persuasive. Contrary to Applicant's arguments, the examiner asserts that based on MPEP §2164, MPEP §§2164.01-2164.06(b) & 2164.08, neither the specification nor the prior art provides sufficient guidance to enable a skilled artisan to practice the full scope of the claimed invention without undue experimentation because:
i. As admitted by Applicant on p. 7 of the response, both full length GFAP and GBDP-38KD are toxic to primary rat cerebrocortical neurons using an MTT mitochondrial assay.
ii. There is no well-established structural and functional relationship or correlation between suppressing astrogliosis or cognitive function in a human subject suffering from all forms of neuroinjury by immunization with the claimed GFAP or the claimed central core GFAP breakdown product (GBDP) of 38KDa, the claimed N-terminal head region with a residue range 1-72 in GFAP-a or the claimed C-terminal tail region with a residue range 378-432 in GFAP-a to achieve active immunization and reducing elevated GFAP levels induced by brain injury at days 20 but not levels of pNF-H or NSE (Examples 4-5, Figures 5A-B) based on preimmunization with the full-length GFAP in an animal at 6-8 weeks, and followed by cortical control impact surgeries at 10-12 weeks as an animal model of traumatic brain injury (TBI) shown in Examples 3-8.
The specification provides no well-established structural and functional relationship or correlation between the intact full length wild type GFAP protein used in examples and the claimed GFAP or a central core GFAP breakdown product (GBDP) of 38KDa, a N-terminal head region with residue range about 1-72 in GFAP-a or a C-terminal tail region with residue range about 378-432 in GFAP-a in reducing elevated GFAP levels induced by brain injury at days 20 but not levels of pNF-H or NSE as shown in Examples 4-5, Figures 5A-B or even in suppressing astrogliosis or cognitive function in a human subject suffering from all forms of neuroinjury.
Based on Applicant’s own admission, pre-immunization with GFAP at 6-8 weeks of mice followed by cortical control impact surgeries at 10-12 weeks as an animal model of traumatic brain injury (TBI) active immunization with GFAP (CCI-GFAP group) resulted in:
a) reducing elevated GFAP levels induced by brain injury at days 20 but not levels of pNF-H or NSE (Examples 4-5, Figures 5A-B); But there was NO difference in the GFAP levels in the CCI mice serum at Day 50 post injury when compared to naive (figure 4C);
b) decreasing p-Tau/t-Tau ratio in cortex and hippocampus in CCI-GFAP as compared to naïve but not at Day 50 (Example 6, Figure 7);
c) pre-immunization with GFAP has NO benefits on histopathological outcomes (figures 8A-8B);
d) intact full length and Calpain-truncated GFAP (GBDP) have neurotoxic effects on cerebrocortical cultures (Example 9, figure 11).
The specification provides no well-established structural and functional relationship or correlation between preimmunization with the claimed GFAP or the claimed GFAP breakdown products in all forms of neuroinjury and the preimmunization with the full-length GFAP in an animal at 6-8 weeks, and followed by cortical control impact surgeries at 10-12 weeks as an animal model of traumatic brain injury (TBI) shown in Examples 3-8 in reducing the elevated GFAP levels induced by brain injury or decreasing p-Tau/t-Tau ratio in cortex and hippocampus in the animal model of TBI as compared to naïve.
There is no well-established structural and functional correlation between all forms of neuroinjury and an animal model of traumatic brain injury (TBI) shown in Examples 3-8 or Examples 10-14. Thus, it is unpredictable whether the claimed GFAP breakdown products can be used for reducing elevated GFAP levels induced by brain injury, or suppressing astrogliosis or improving cognitive function in all forms of neuroinjury, indicating that undue experimentation is required by a skilled artisan to perform while practicing the claimed invention.
iii. There is no well-established structural and functional relationship or correlation between treatment with the claimed structurally and functionally undefined anti-GFAP IgG or IgM antibody or the claimed structurally and functionally undefined GFAP-binding aptamer binding to an antigen recited in claims 1 and 11 in all forms of neuroinjury and the treatment of an animal model of traumatic brain injury (TBI) with defined mouse monoclonal anti-GFAP antibody cocktail (clones 1B4, 4A11, 2E1 from BD pharmigen) shown in Examples 10-14.
The specification provides no well-established structural and functional relationship or correlation between the defined mouse monoclonal anti-GFAP antibody cocktail (clones 1B4, 4A11, 2E1 from BD pharmigen) used in Examples 10-14 and the claimed anti-GFAP IgG or IgM antibody or GFAP-binding aptamer that binds to an antigen selected from the group consisting of a full-length GFAP isoform, a GFAP-a residue 1-432, a central core GFAP breakdown product with a residue range 79-383 in GFAPa, an N-terminal head region of GFAPa with a residue range 1-72 in GFAPa, and a C-terminal tail region of GFAPa with a residue range 378-432 in GFAPa.
Based on Applicant’s own admission, administration of an anti-GFAP monoclonal antibody (mouse monoclonal anti-GFAP antibody cocktail: clones 1B4, 4A11, 2E1 from BD pharmigen) to an animal model of TBI (CCI-anti-GFAP mAb group) resulted in:
a) in an anxiety behavior test, there is NO difference in distance traveled and velocity of mouse movement in both CCI and CCI+anti-GFAP mAb; but CCI+GFAP mAb group spent more time in the open arms, indicating reduced anxiety behavior (Example 10, figure 12);
b) in Y-maze tests, CCI+GFAP mAb group spent more time than the CCI group in the novel arm and less time in the other two arms and in the MWM tests, CCI+GFAP mAb group spent more time than the CCI group in the target quadrant area (Example 11, figures 13-14);
c) both CCI and CCI+GFAP mAb group showed the same GFAP levels but CCI+GFAP mAb group showed reduced GBDP levels (Example 12, figure 15);
d) CCI+GFAP mAb group showed a reduced p-Tau/t-Tau ratio as compared to naive (Example 13, Figure 16);
e) CCI+GFAP mAb group showed reduced Tau released in serum (Example 14, Figure 17).
There is no well-established structural and functional correlation between all forms of neuroinjury and an animal model of traumatic brain injury (TBI) shown in Examples 3-8 or Examples 10-14.
There is no well-established structural and functional relationship between the claimed structurally and functionally undefined anti-GFAP IgG or IgM antibody or the claimed structurally and functionally undefined GFAP-binding aptamer binding to the recited antigens and the mouse monoclonal anti-GFAP antibody cocktail (clones 1B4, 4A11, 2E1 from BD pharmigen) used in Examples 10-14.
The specification fails to teach what structures/amino acid sequences for the claimed anti-GFAP IgG or IgM antibody or the claimed structurally and functionally undefined GFAP-binding aptamer binding to the recited antigens including a full-length GFAP isoform, a GFAP-a residue 1-432, a central core GFAP breakdown product with a residue range 79-383 in GFAPa, an N-terminal head region of GFAPa with a residue range a 1-72 in GFAPa, and a C-terminal tail region of GFAPa with a residue range 378-432 in GFAPa are. Thus, it is unpredictable what other anti-GFAP IgG or IgM antibody or the claimed structurally and functionally undefined GFAP-binding aptamer binding to the recited antigens including a full-length GFAP isoform, a GFAP-a residue 1-432, a central core GFAP breakdown product with a residue range 79-383 in GFAPa, an N-terminal head region of GFAPa with a residue range 1-72 in GFAPa, and a C-terminal tail region of GFAPa with a residue range 378-432 in GFAPa are, and whether they can be used to reduce GBDP levels, or to suppress astrogliosis or improve cognitive function in all forms of neuroinjury, indicating that undue experimentation is required by a skilled artisan to perform while practicing the claimed invention.
Taken together, since the structural and functional relationship between the claimed GFAP and the claimed GFAP breakdown products recited in claims 1 and 11 in all forms of neuroinjury and the full length GFAP used in an animal model of TBI shown in Examples 3-8 is unknown, and the structural and functional relationship between the claimed anti-GFAP IgG or IgM antibody or GFAP-binding aptamers binding to recited antigens and the mouse monoclonal anti-GFAP antibody cocktail (clones 1B4, 4A11, 2E1 from BD pharmigen) used in Examples 10-14 is also unknown, a skilled artisan cannot contemplate how to make and use the claimed invention without undue experimentation.
Therefore, in view of the breadth of the claims, the lack of guidance in the specification, the limited examples, the unpredictability of inventions, and the current status of the art, undue experimentation would be required by a skilled artisan to perform in order to practice the full scope of the claimed invention as it pertains to a method for suppressing astrogliosis or statistically significantly improving cognitive function in a human subject suffering from a neuroinjury by administering the claimed GFAP or the claimed GFAP breakdown products or the claimed anti-GFAP IgG or IgM or GFAP-binding aptamer binding to recited antigens to the human subject.
Accordingly, the rejection of claims 1, 3 and 11-12 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, lack of enablement is maintained.
Claim Rejections - 35 USC § 112
8. Claims 1, 3 and 11-12 stand 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. The rejection is maintained for the reasons of record and the reasons set forth below
Briefly, Claims 1, 3 and 11-12 as amended encompass using a genus of structurally and functionally undefined GFAP, or a genus of structurally and functionally undefined central core GFAP breakdown product (GBDP) of 38KDa, a genus of structurally and functionally undefined N-terminal head region with a residue range 1-72 in GFAP-a or a genus of structurally and functionally undefined C-terminal tail region with a residue range 378-432 in GFAP-a to achieve active immunization for suppressing astrogliosis or improving cognitive function in a human subject suffering from a neuroinjury. Claims 1, 3 and 11-12 as amended also encompass using a genus of structurally and functionally undefined anti-GFAP IgG or IgM antibody or a genus of structurally and functionally undefined GFAP-binding aptamer binding to an antigen selected from the group consisting of a full-length GFAP isoform, a GFAP-a residue 1-432, a central core GFAP breakdown product with a residue range 79-383 in GFAPa, an N-terminal head region of GFAPa with a residue range 1-72 in GFAPa, and a C-terminal tail region of GFAPa with a residue range 378-432 in GFAPa to achieve passive immunization for suppressing astrogliosis or improving cognitive function in a human subject suffering from a neuroinjury.
Based on paragraph [0045] of the published specification, the claimed “GFAP” encompasses isoforms of GFAP, variants, intermediates filament protein or fragments thereof.
[0045] As used herein, the term “GFAP” refers to intact glial fibrillary acidic protein, an intermediate filament protein encoded by the GFAP gene in humans and expressed in the central nervous system, primarily in astrocytes. All isoforms of the GFAP protein are included in this definition. As used herein, the term also refers to breakdown products of GFAP, including natural and synthetic peptides derived from the sequence of GFAP. Therefore, “GFAP or a fragment thereof” refers to full length GFAP isoforms or any breakdown product, for example, the central core breakdown product GFAP-38K (with residue range about 79-383 in GFAP-α), the N-terminal head region with residue range about 1-72 in GFAP-α, and the C-terminal tail region with residue range about 378-432 in GFAP-α, i.e., the truncated forms of GFAP with apparent molecular weights of about 44 kDa, 42 kDa, 40 kDa and 38 kDa.
Applicant has not disclosed sufficient species for using the broad genus of GFAP, the broad genus of central core GFAP breakdown product (GBDP) of 38KDa, the broad genus of N-terminal head region with residue range 1-72 in GFAP-a, the broad genus of C-terminal tail region with residue range 378-432 in GFAP-a to achieve active immunization to suppress astrogliosis or improve cognitive function in a genus of neuroinjury.
Applicant has also not disclosed sufficient species for the broad genus of anti-GFAP IgG or IgM antibody or the broad genus of GFAP-binding aptamer binding to a full-length GFAP isoform, a GFAP-a residue 1-432, a central core GFAP breakdown product with a residue range 79-383 in GFAPa, an N-terminal head region of GFAPa with a residue range 1-72 in GFAPa, and a C-terminal tail region of GFAPa with a residue range 378-432 in GFAPa to achieve passive immunization to suppress astrogliosis or improve cognitive function in a genus of neuroinjury.
Response to Arguments
On p. 8 of the response, Applicant argues that i) the rejection has been overcome in view of amendment to claims 1 and 11. ii) a skilled artisan would know Applicant is in possession of the claimed methods recited in amended claims 1 and 11 based on the teachings of specific sequence mapping to the GFAP-a protein sequence, the GFP-38K (residue range about 79-383), the N-terminal head region (residues 1-72) and the C-terminal tail region (residues 378-432).
Applicant's arguments have been fully considered but they are not found persuasive. Contrary to Applicant's arguments, the examiner asserts that based on MPEP §2163, MPEP §§2163.01-2163.03, the specification fails to provide sufficient description or information or evidence to demonstrate that Applicant is in possession of the claimed method of suppressing astrogliosis or improving cognitive function by administering the claimed genus of GFAP or the claimed genus of central core GFAP breakdown product (GBDP) of 38KDa, the claimed genus of N-terminal head region with residue range about 1-72 in GFAP-a, the claimed genus of C-terminal tail region with residue range about 378-432 in GFAP-a, or the claimed genus of anti-GFAP IgG or IgM antibody or the broad genus of GFAP-binding aptamer binding to a full-length GFAP isoform, a GFAP-a residue 1-432, a central core GFAP breakdown product with a residue range about 79-383 in GFAPa, an N-terminal head region of GFAPa with a residue range about 1-72 in GFAPa, and a C-terminal tail region of GFAPa with a residue range about 378-432 in GFAPa to the human subject suffering from all forms of neuroinjury because:
i. Based on paragraph [0045] of the published specification, the claimed “GFAP” encompasses isoforms of GFAP, variants, intermediates filament protein or fragments thereof.
[0045] As used herein, the term “GFAP” refers to intact glial fibrillary acidic protein, an intermediate filament protein encoded by the GFAP gene in humans and expressed in the central nervous system, primarily in astrocytes. All isoforms of the GFAP protein are included in this definition. As used herein, the term also refers to breakdown products of GFAP, including natural and synthetic peptides derived from the sequence of GFAP. Therefore, “GFAP or a fragment thereof” refers to full length GFAP isoforms or any breakdown product, for example, the central core breakdown product GFAP-38K (with residue range about 79-383 in GFAP-α), the N-terminal head region with residue range about 1-72 in GFAP-α, and the C-terminal tail region with residue range about 378-432 in GFAP-α, i.e., the truncated forms of GFAP with apparent molecular weights of about 44 kDa, 42 kDa, 40 kDa and 38 kDa.
ii. The specification provides no well-established structural and functional relationship or correlation between immunizing in an animal model of TBI with the intact full length wild type GFAP shown in Examples 3-8 and immunization with the claimed genus of GFAP or the claimed GFAP breakdown products (GBDPs) including central core GFAP breakdown product (GBDP) of 38KDa, N-terminal head region with a residue range 1-72 in GFAP-a, or C-terminal tail region with a residue range 378-432 in GFAP-a in an animal model of TBI or other forms of neuroinjury.
The structural and functional relationship or correlation between immunizing in an animal model of TBI with the intact full length wild type GFAP shown in Examples 3-8 and immunization with the claimed genus of GFAP in an animal model of TBI or other forms of neuroinjury is unknown because the claimed “GFAP” encompasses GFAP isoforms, variants, intermediates filament protein or fragments thereof in view of paragraph [0045] of the published specification. The structural and functional relationship or correlation between immunizing in an animal model of TBI with the intact full length wild type GFAP shown in Examples 3-8 and immunizing with isoforms, variants, intermediates filament protein or fragments thereof in an animal model of TBI or other forms of neuroinjury is unknown.
Since the common characteristics/features of the claimed genus of GFAP, the claimed genus of GBDPs including central core GFAP breakdown product (GBDP) of 38KDa, N-terminal head region with a residue range 1-72 in GFAP-a, or C-terminal tail region with a residue range 378-432 in GFAP-a recited in claims 1 and 11 are unknown, a skilled artisan cannot envision the functional correlations of the claimed genera 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 anti-GFAP IgG or IgM or GFAP-binding aptamers binding to the antigen recited in claims 1 and 11 for suppressing astrogliosis or statistically significantly improving cognitive function in all forms of neuroinjury.
iii. The structural and functional relationship or correlation between administration of the mouse monoclonal anti-GFAP antibody cocktail (clones 1B4, 4A11, 2E1 from BD pharmigen) used in Examples 10-14 and the claimed genus of anti-GFAP IgG or IgM or GFAP-binding aptamers binding to the antigen recited in claims 1 and 11 in an animal model of TBI or other forms of neuroinjury is unknown.
Applicant has provided no structures or sequences sufficiently detailed to show that he/she was in possession of using the claimed genus of anti-GFAP IgG or IgM or GFAP-binding aptamers binding to the antigen recited in claims 1 and 11 in the claimed invention as a whole. There was also no known or disclosed correlation between the required function (i.e. binding to the antigen recited in claims 1 and 11 including a full-length GFAP isoform, a GFAP-a residue 1-432, a central core GFAP breakdown product with a residue range 79-383 in GFAPa, an N-terminal head region of GFAPa with a residue range 1-72 in GFAPa, and a C-terminal tail region of GFAPa with a residue range 378-432 in GFAPa) and any particular structure or sequence.
Applicant has not disclosed sufficient species for the broad genus of anti-GFAP IgG or IgM or GFAP-binding aptamers binding to the antigen recited in claims 1 and 11. The specification only discloses administering the defined mouse monoclonal anti-GFAP antibody cocktail (clones 1B4, 4A11, 2E1 from BD pharmigen) in an animal model of TBI as shown in Examples 10-14. However, the specification fails to demonstrate that Applicant is in possession of using the claimed genus of anti-GFAP IgG or IgM or GFAP-binding aptamers binding to the antigen recited in claims 1 and 11 for suppressing astrogliosis or statistically significantly improving cognitive function in all forms of neuroinjury.
In light of Amgen, Inc. v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), describing a “fully characterized antigen” for an antibody is no longer adequate on its own to demonstrate possession of the antibody. Based on MPEP§2161.01 and 2163, the USPTO guidance regarding written description requirement of 35 U.S.C.§C112 (a), specifically concerning the written description requirement for claims drawn to antibodies and Federal Circuit decisions, when an antibody is claimed, 35USC112(a) requires adequate written description of the antibody itself. See Amgen 872 F.3d at 1378-79.
The court of the Federal Circuit also stressed that the “newly characterized antigen" test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. See Amgen, 872 F.3d at 1378-79, quoting Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1345 (Fed. Cir.2010). In view of the Amgen decision, adequate written description of a newly characterized antigen alone should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional.
The specification’s general reference to anti-GFAP IgG or IgM or GFAP-binding aptamers binding to the antigen recited in claims 1 and 11 does not clearly suggest any particular sequences that can be used in order to result in the claimed anti-GFAP IgG or IgM or GFAP-binding aptamers binding to the antigen recited in claims 1 and 11 or the claimed features. As such, he cannot possibly have possessed using the entire genus in the claimed methods.
Since the common characteristics/features of other anti-GFAP IgG or IgM or GFAP-binding aptamers binding to the antigen recited in claims 1 and 11 are unknown, a skilled artisan cannot envision 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 anti-GFAP IgG or IgM or GFAP-binding aptamers binding to the antigen recited in claims 1 and 11 for suppressing astrogliosis or statistically significantly improving cognitive function in all forms of neuroinjury.
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 GFAP, GBDPs including central core GFAP breakdown product (GBDP) of 38KDa, N-terminal head region with a residue range 1-72 in GFAP-a, or C-terminal tail region with a residue range 378-432 in GFAP-a and the genus of anti-GFAP IgG or IgM antibody or GFAP-binding aptamers binding to the antigens recited in claims 1 and 11, 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 methods have 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.
Accordingly, the rejection of claims 1, 3 and 11-12 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is maintained.
Claim Rejections - 35 USC § 102
9. 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, 3 and 11-12 stand rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lafaye et al. (US10155054). The rejection is maintained for the reasons of record and the reasons set forth below.
Briefly, Lafaye (US10155054) teaches a pharmaceutical composition comprising an anti-GFAP antibody or a VHH domain against GFAP (i.e. anti-GFAP antibody IgG) (see col. 7, line 30-col. 9, line 2; col. 18-22, Examples 3-4) for treatment of a disorder mediated by GFAPs including traumatic brain injury (TBI), gliosis or astrocytoma, or brain cancers or neurodegenerative disorders including AD (col. 8, lines 16-31) ; immunizing with GFAP to generate an anti-GFAP (col.2, lines 26-29;lines 60-67), and a method comprising administering to a human subject the composition comprising the anti-GFAP antibody or anti-GFAP VHH antibody and a pharmaceutically acceptable carrier (see claims 40-43), which meet the limitations recited in instant claims 1, 3 and 11-12. The limitations “suppressing astrogliosis” and “improving cognitive function” recited in the preamble of claims 1 and 11 respectively are intended use and are inherent results of administration of anti-GFAP VHH antibody identical to instant claims. If the claimed method can achieve “suppressing astrogliosis” and “improving cognitive function”, the Lafave’s method using the same material (i.e. anti-GFAP IgG) and the same active step (administering to a human subject) in the same patient population (i.e. patients with TBI or gliosis, astrocytoma or neurodegenerative diseases including AD, which is a neuroinjury) as instantly claimed can achieve the same effects recited in the preamble of the claims. See Pitney Bowes, Inc. v. Hewlett-Packard Co., 182 F.3d 1298, 1305, 51 USPQ2d 1161, 1165 (Fed. Cir. 1999); Rowe v. Dror, 112 F.3d 473, 478, 42 USPQ2d 1550, 1553 (Fed. Cir. 1997); In re Schreiber, 128 F.3d 1473, 1477, 44 USPQ2d 1429, 1431 (Fed. Cir. 1997) and MPEP §2111.02-I. Thus, claims 1, 3 and 11-12 are anticipated by Lafaye et al. (US10155054).
Response to Arguments
On p. 8-9 of the response, Applicant argues that: i) the rejection has been overcome in view of amendment to the claims 1 and 11. ii) Lafaye does not anticipates instant claims because Lafaye is silent regarding antibodies binding to GBDPs.
Applicant's arguments have been fully considered but they are not found persuasive. Contrary to Applicant's arguments, the examiner asserts that based on MPEP §2131, Lafaye does teach the claimed methods because:
i. instant claims 1, 3 and 11-12 also encompass suppressing astrogliosis or improving cognitive function in a human subject suffering from a neuroinjury using an anti-GFAP IgG or IgM antibody binding to a GFAP-a residue 1-432 to achieve passive immunization.
ii. The anti-GFAP antibody or a VHH domain against GFAP (i.e. anti-GFAP antibody IgG) (see col. 7, line 30-col. 9, line 2; col. 18-22, Examples 3-4) disclosed by Lafaye bind to a GFAP-a residue 1-432. Thus, the anti-GFAP antibody or a VHH domain against GFA and the method for treatment of a disorder mediated by GFAPs including traumatic brain injury (TBI), gliosis or astrocytoma, or brain cancers or neurodegenerative disorders including AD (seecol. 8, lines 16-31; see claims 40-43)) disclosed by Lafaye meets the limitations recited in instant claims 1, 3 and 11-12.
Accordingly, the rejection of claims 1, 3 and 11-12 under 35 U.S.C. 102(a)(1) as being anticipated by Lafaye is maintained.
Conclusion
10. NO CLAIM IS ALLOWED.
11. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Van Eyk et al. (US12007395) teach a method of diagnosis of different neurodegenerative diseases and a kit comprising anti-GFAP antibodies or GFAP-binding aptamers for diagnosis (see col.2, lines 35-38; col.6, lines 20; col. 20, lines 45-57).
12. THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
13. 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.
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Chang-Yu Wang
October 14, 2026
/CHANG-YU WANG/Primary Examiner, Art Unit 1675
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