DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Rejections - 35 USC § 112
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 33-34, and 36 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 detecting AAV antibodies, does not reasonably provide enablement for gene therapy. 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.
The specification does not teach any specifics about treating a subject in need of gene therapy.
The specification is enabled for detecting AAV antibodies.
The state of the art for gene therapy is unpredictable.
There is no established gene therapy treatment for HIV. Kahn et al. (Clinical Immunology, Volume 255, October 2023, 109741) teach “CCR5 gene-editing using CRISPR/Cas9 to reproduce the ∆32 mutations certainly requires optimization, thorough in vitro testing, and preclinical validation.” (Conclusion).
Thus, the lack of teaching in the specification on gene therapy, the complexity of the art, and the lack of established gene therapy treatment for HIV, the full scope of the claims are not enabled.
-Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 2-4 and 16-18 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception of an abstract idea without significantly more. The claims are drawn to a method of detecting AAV using a mathematical formula or equation to determine the cut factor. The cut factor is not an active method step but a value used in the method. The claims are drawn to a mental step to determine the factor value. This judicial exception is not integrated into a practical application because the value can be read off of a piece of paper. Claims requiring mathematical algorithms have been found by the courts to be an abstract idea, see Benson, 409 U.S. at 64, 175 USPQ at 674;Flook, 437 U.S. at 585, 198 USPQ at 195; and Bilski, 561 U.S. at 599, 95 USPQ2d at 1004-05.
The instant claims are also analyzed to determine whether additionally required elements are sufficient to amount to more than the judicial exception. The claims additionally require detecting AAV antibodies. The detecting of AAV antibodies is known in the as demonstrated by the art use below, High et al. (2019/0192693). Thus, the claims recite additional limitations where the mathematical algorithm is implemented. However, these materials are conventional in the prior art.
Therefore, the claims also do not include additional elements that are
sufficient to amount to significantly more than the judicial exception of the abstract idea and are not patent eligible.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim(s) 1-4, 7, 10, 14-18, 21, and 24 is/are rejected under 35 U.S.C. 103 as being unpatentable over High et al. (20190192693) and Daniel et al. (US20140242061A1).
For claim 1, High et al. discloses a method of detecting anti-adeno-associated virus (anti-AAV) antibodies in a test subject (methods include detection of primary immune complexes, Para. [0123]; antibodies to one AAV as compared to another AAV, Para. [0061]; test composition suspected of containing AP protein, such as a clinical sample (e.g., a biological sample obtained from the subject), Para. (0125)), the method comprising (a) providing a test sample obtained from the test subject (a clinical sample (e.g., a biological sample obtained from the subject), Para. [0125]); (b) contacting the test sample with a test AAV capsid (capsids are believed to bind to or react with antibodies against the AAV vectors,. Para. [0094]; the samples suspected of containing the antigen are immobilized onto the well surface and/or then contacted with binding agents, Para. [0126]), wherein the test AAV capsid has been immobilized on a test solid support (capsids are believed to bind to or react with antibodies against the AAV vectors, Para. [0094]; samples suspected of containing the antigen are immobilized onto the well surface and/or then contacted with binding agents, Para. [0126}); (c) contacting the test sample-contacted immobilized test AAV capsid with a test secondary antibody, wherein the test secondary antibody comprises a test detectable label (antibody or antibody fragment) may itself be linked to a detectable label, wherein one would then simply detect this label, thereby allowing the amount of the primary immune complexes in the composition to be determined and/or quantified. Alternatively, the first antibody that becomes bound within the primary immune complexes may be detected by means of a second binding ligand that has binding affinity for the antibody. In these cases, the second binding ligand. may be linked to a detectable label. The second binding ligand is itself often an antibody, which may thus be termed a “secondary” antibody, Para. [0122]; capsids are believed to bind to or react with antibodies against the AAV vectors, Para. [0094]; samples suspected of containing the antigen are immobilized onto the well surface and/or then contacted with binding agents, Para. [0126]); and (d) detecting the test detectable label ({detection may also be achieved by the addition of a second antibody, followed by the addition of a third antibody that has binding affinity for the second antibody, with the third antibody being linked to a detectable label, Para. [0125]); then the test subject comprises anti-AAV antibodies (a protein detection molecule (i.e., binding ligand, such as an antibody or antibody fragment) may itself be linked to a detectable label, wherein one would then simply detect this label, thereby allowing the amount of the primary immune complexes in the composition to be determined and/or quantified, Para. [0122]; antibodies to one AAV as compared to another AAV, Para. [0061]; test composition suspected of containing AP protein, such as a clinical sample (e.g., a biological sample obtained from the subject), Para. [0125]); then the test subject does not comprise anti-AAV antibodies (antibody, under effective conditions and for a period of time sufficient to allow the formation of secondary immune complexes. The secondary immune complexes are then generally washed to remove any non-specifically bound labeled secondary antibodies or ligands, and the remaining label in the secondary immune complexes is then detected, Para. [0122]; antibodies to one AAV as compared to another AAV, Para. [0061]; test composition suspected of containing AP protein, such as a clinical sample (e.g., a biological sample obtained from the subject), Para. [(0125)).
For claims 2-4, the cut point factor of claim 1 is a fixed value and thus the claims 2-4 are product by process claims that only require a value.
For claims 7, 21, and 24, the AAV used can be AAV6 (paragraphs 24-29 and 60-66), thus those would be detected and claim 24, immune complexes are then generally washed to remove any non-specifically bound labeled secondary antibodies or ligands, and the remaining label in the secondary immune complexes is then detected, Para. [0122] and the choice of washing and when to wash can be determined through routine experimentation.
For claim 10, immune complexes are then generally washed to remove any non-specifically bound labeled secondary antibodies or ligands, and the remaining label in the secondary immune complexes is then detected, Para. [0122] and the choice of washing and when to wash can be determined through routine experimentation.
For claim 14, it would be obvious to one of ordinary skill in the art before the effective filing date to test before AAV administration to avoid false positives caused by the administered dose.
For claim 15, High et al. discloses a method of detecting anti-adeno-associated virus (anti-AAV) antibodies in a test subject (methods include detection of primary immune complexes, Para. [0123]; antibodies to one AAV as compared to another AAV, Para. [0061]; test composition suspected of containing AP protein, such as a clinical sample (e.g., a biological sample obtained from the subject), Para. [0125}), the method comprising (a) providing a first test sample and a second test sample obtained from the test subject (a clinical sample (e.g., a biological sample obtained from the subject), Para. [0125]); (b) contacting the second test sample with a test soluble AAV capsid (capsids are believed to bind to or react with antibodies against the AAV vectors, Para. [0094]; the samples suspected of containing the antigen are immobilized onto the well surface and/or then contacted with binding agents, Para. [0126]): (c) contacting the first test sample with a first test immobilized AAV capsid, wherein the first test immobilized AAV capsid has been immobilized on a first test solid support (capsids are believed to bind to or react with antibodies against the AAV vectors, Para. [0094]; samples suspected of containing the antigen are immobilized onto the well surface and/or then contacted with binding agents, Para. [0126]); (d) contacting the mixture of the second test sample and the soluble test AAV capsid with a second test immobilized AAV capsid, wherein the second test immobilized AAV capsid has been immobilized on a second test solid support; (e) contacting the first test sample-contacted first test immobilized AAV capsid with a first test secondary antibody, wherein the first test secondary antibody comprises a first test detectable label (antibody or antibody fragment) may itself be linked to a detectable label, wherein one would then simply detect this label, thereby allowing the amount of the primary immune complexes in the composition to be determined and/or quantified. Alternatively, the first antibody that becomes bound within the primary immune complexes may be detected by means of a second binding ligand that has binding affinity for the antibody. In these cases, the second binding ligand may be linked to a detectable label. The second binding ligand is itself often an antibody, which may thus be termed a "secondary" antibody, Para. [0122]; capsids are believed to bind to or react with antibodies against the AAV vectors, Para. [0094]; samples suspected of containing the antigen are immobilized onto the well surface and/or then contacted with binding agents, Para. [0126)]); (f) contacting the mixture-contacted second test immobilized AAV capsid with a second test secondary antibody, wherein the second test secondary antibody comprises a second test detectable label, wherein the second test secondary antibody is the same as the first secondary antibody and the first test detectable label is the same as the second test detectable label (antibody or antibody fragment) may itself be linked to a detectable label, wherein one would then simply detect this label, thereby allowing the amount of the primary immune complexes in the composition to be determined and/or quantified. Alternatively, the first antibody that becomes bound within the primary immune complexes may be detected by means of a second binding ligand that has binding affinity for the antibody. In these cases, the second binding ligand may be linked to a detectable label. The second binding ligand is itself often an antibody, which may thus be termed a "secondary" antibody, Para. (0122}: capsids are believed to bind to or react with antibodies against the AAV vectors, Para. (0094); samples suspected of containing the antigen are immobilized onto the well surface and/or then contacted with binding agents, Para. [0126]); and (g) detecting the first and second test detectable labels ([detection may also be achieved by the addition of a second antibody, followed by the addition of a third antibody that has binding affinity for the second antibody, with the third antibody being linked to a detectable label, Para. [0125]); then the subject comprises anti AAV antibodies (a protein detection molecule (i.e., binding ligand, such as an antibody or antibody fragment) may itself be linked to a detectable label, wherein one would then simply detect this label, thereby allowing the amount of the primary immune complexes in the composition to be determined and/or quantified, Para. [0122}; antibodies to one AAV as compared to another AAV, Para. [0061]; test composition suspected of containing AP protein, such as a clinical sample (e.g., a biological sample obtained from the subject), Para. (0125]); and wherein if the amount of second label detected is reduced by less than the cut point compared to the amount of first label detected (antibody, under effective conditions and for a period of time sufficient to allow the formation of secondary immune complexes. The secondary immune complexes are then generally washed to remove any non-specifically bound labeled secondary antibodies or ligands, and the remaining label in the secondary immune complexes is then detected, Para. [0122]; antibodies to one AAV as compared to another AAV, Para. [0061]; test composition suspected of containing AP protein, such as a clinical sample (e.g., a biological sample obtained from the subject), Para. [0125]). High et al. fails to explicitly disclose wherein if the amount of second label detected is reduced by a cut point percentage or more compared to the amount of first label detected. Daniel et al. is in the field of methods of evaluating ELISA or radioimmunoprecipitation assay (RIP)), for the presence of antibodies (Para. {0018)), and teaches wherein if an amount of second label detected is reduced by a cut point percentage or more compared to the amount of first label detected ([t]he assay cut point was determined from individual healthy human donor sera (N=52) and enzyme replacement therapy-naive Gaucher patients (N=35). The cut point for the velaglucerase alfa and imiglucerase neutralizing antibody assays was defined as inhibition >20.0 percent based on these 87 samples. Therefore, a patient sample was considered to be negative for inhibitory antibodies if the level of inhibition observed was ?20.0 percent and to be positive if inhibition >20.0 percent, Para. [0934]; the detected label is quantified to a value and compared to a control, e.g., a negative control, wherein if the value of detected label is greater than the negative control, the sample contains ...antibody, Para. [0194)). It would have been obvious to one of ordinary skill in the art at the time of the invention to modify High et al. with the teaching of Daniel et al. for the purpose of detecting antibodies in patient samples (Daniel et al., Para. [0194]).
For claims 16-18, they are obvious as explained for claims 2-4 above and in Daniel et al.
High et al. fails to explicitly disclose wherein if the label detected with a normalized response relative to a negative control is greater than or equal to a cut point factor; and wherein if the label is detected with a normalized response relative to a negative control is less than the cut point factor.
For claims 1-4 and 15-18, Daniel et al. is in the field of methods of evaluating ELISA or radioimmunoprecipitation assay (RIP), for the presence of antibodies (Para. [0018)), and teaches wherein if the label detected with a normalized response relative to a negative control is greater than or equal to a cut point factor; and wherein if the label is detected with a normalized response relative to a negative control is less than the cut point factor ([t]he assay cut point was determined from individual healthy human donor sera (N=52) and enzyme replacement therapy-naive Gaucher patients (N=35). The cut point for the velaglucerase alfa and imiglucerase neutralizing antibody assays was defined as inhibition >20.0 percent based on these 87 samples. Therefore, a patient sample was considered to be negative for inhibitory antibodies if the level of inhibition observed was 720.0 percent and to be positive if inhibition >20.0 percent, Para. [0934]; the detected label is quantified to a value and compared to a control, e.g., a negative control, wherein if the value of detected label is greater than the negative control, the sample contains ...antibody, Para. [0194]). And is silent on wherein the outlier reference samples are removed using the criteria [Q1-1.5*(Q3-Q1),Q3+1.5*(Q3-Q1)]. However, Daniel et al. teaches a relationship between removing outlier reference samples ([t]he assay cut point was determined from individual healthy human donor sera (N=52) and enzyme replacement therapy-naive Gaucher patients (N=35). The cut point for the velaglucerase alfa and imiglucerase neutralizing antibody assays was defined as inhibition >20.0 percent based on these 87 samples. Therefore, a patient sample was considered to be negative for inhibitory antibodies if the level of inhibition observed was 720.0 percent and to be positive if inhibition >20.0 percent, Para. [0934]). Further, deriving the relationship between removing outlier reference samples as recited in the claim is a matter of mere mathematical manipulation, a known practice in the art.
The level of skill in the art of antibody-antigen binding assays is high.
One of ordinary skill in the art would be able to determine cut point values by any art known method and have the expectation of success as it is known in the art. One of ordinary skill in the art would be motivated to determine a cut point factor they are known to define the determination the calling of positive or negative as taught in Daniel et al.
It would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to modify High et al. with the teaching of cut factors of Daniel et al. for the purpose of detecting antibodies in patient samples.
Conclusion
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MYRON G. HILL
Examiner
Art Unit 1671
/M.G.H/Examiner, Art Unit 1671
/Shanon A. Foley/Primary Examiner, Art Unit 1671