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
Request for Continued Examination
Status of Application/Amendment/Claims
Applicant's response filed 01/07/2026 has been considered. Rejections and/or objections not reiterated from the previous office action mailed 10/07/2025 are hereby withdrawn. The following rejections and/or objections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
With entry of the amendment filed on 01/07/2026, claims 1-15, 17-28, 30, 31, 35 and 36 are pending in the application.
New Claim Rejections – necessitated by claim amendments
Claim Rejections - 35 USC § 112
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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.
Claim 36 is 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
describing associations of HSD17B13 splice variant rs72613567:TA with liver pathology and clinical quantitative traits and diagnoses wherein this was correlated with a lower odds of having chronic liver diseases such as NASH and fibrosis,
expression of HSD17B13 in liver cells and
modification of a mouse HSD17B13 using CRISPR/Cas9
does not reasonably provide enablement for
methods of using CRISPR Cas 9 to generate a targeted genetic modification in the HSD17B13 gene thereby having a therapeutic or prophylactic effect against the chronic liver disease in a subject who is not a carrier f the HSD17B13 rs72613567 variant or
methods of using CRISPR Cas 9 to cause a loss of function of a HSD17B13 splice variant rs72613567:TA thereby having a therapeutic or prophylactic effect against the chronic liver disease in a subject who is not a carrier f the HSD17B13 rs72613567 variant.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
The following factors have been considered in the analysis of enablement: (1) the breadth of the claims, (2) the nature of the invention, (3) the state of the prior art, (4) the level of one of ordinary skill, (5) the level of predictability in the art, (6) the amount of direction provided by the inventor, (7) the existence of working examples, (8) the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The breadth of the claims and nature of the invention:
The claims are drawn to methods of using a CRISPR/Cas 9 system to cause a targeted genetic modification in HSD17B13 gene where this has a therapeutic or prophylactic effect against a chronic liver disease in a subject who is not a carrier f the HSD17B13 rs72613567 variant. The nature of the invention relies upon causing any type of genetic modification in the HSD17B13 gene in a liver cell which would provide therapeutic or prophylactic effect against a chronic liver disease in a subject.
Whether the specification would have been enabling as of the filing date involves consideration of the nature of the invention, the state of the prior art, and the level of skill in the art. The state of the prior art is what one skilled in the art would have known, at the time the application was filed, about the subject matter to which the claimed invention pertains. The relative skill of those in the art refers to the skill of those in the art in relation to the subject matter to which the claimed invention pertains at the time the application was filed. See MPEP § 2164.05(b). The state of the prior art provides evidence for the degree of predictability in the art and is related to the amount of direction or guidance needed in the specification as filed to meet the enablement requirement. The state of the prior art is also related to the need for working examples in the specification.
The state of the prior art:
A thorough review of the patent and non-patent literature indicates that the state of the art for any known HSD17B13 genetic variant which plays a protective role against any chronic liver disease is unclear and unproven at the time of filing of the instant application. The prior art describes an association between HSD17B13 and fatty liver development and liver disease such as NFALD. Rotman et al. ("Identification ofHSD17B13 and RORA as Genes Involved in Pathogenesis of Nonalcoholic Fatty Liver Disease: 145." Hepatology 56 (2012): 265A cited on 892 mailed 01/24/2025), describes nonalcoholic fatty liver disease (NFALD) as being associated with liver enzyme abnormalities and found HSD17B13, a liver-specific lipid droplet protein, as associated with NAFLD histology and pathogenesis (see Results). Zhang et al. ("Omic studies reveal the pathogenic lipid droplet proteins in non-alcoholic fatty liver." (2016) cited on 892 mailed 01/24/2025), discuss a possible mechanism by which the protein 17β-hydroxysteroid dehydrogenase 13 (17βHSD13) may promote the development of NAFLD. Both references have been previously discussed in depth in O.A. mailed 01/24/2025.
The non-patent literature, after the filing of the instant application, describes the variant rs72613567:TA of the HSD17B13 as being associated with a reduced risk of chronic liver disease. Abul-Husn et al., an inventor, )"A protein-truncating HSD17B13 variant and protection from chronic liver disease." New England Journal of Medicine 378.12 (2018): 1096-1106) teach a loss-of-function variant rs72613567:TA in the HSD17B13 gene is associated with a reduced risk of chronic liver disease and of progression from steatosis to steatohepatitis (see page 1096 and discussion page 1105). Ma et al. ("17‐beta hydroxysteroid dehydrogenase 13 is a hepatic retinol dehydrogenase associated with histological features of nonalcoholic fatty liver disease." Hepatology 69.4 (2019): 1504-1519) describes several SNPs of HSD17B13 are associated with non-alcoholic fatty liver disease (NAFLD) (see table 1). The post-filing reference of Motomura et al. ("Is HSD17B13 genetic variant a protector for liver dysfunction? Future perspective as a potential therapeutic target." Journal of Personalized Medicine 11.7 (2021): 619) describes the roles of certain variants of HSD17B13 (as discussed above for references by Abul-Husn et al. and Ma et al.) but concludes the protective role of these newly discovered genetic variants of HSD17B13 needs further study. Experiments conducted in knock-in/knock-out models of mice produced results that conflicted with those conducted in cell line models. Additionally, clinical samples have varying genetic and lifestyle backgrounds, making it difficult to compare between approaches (conclusion page 9).
While the state of the post-filing art does provide evidence that a variant of HSD17B13, rs72613567:TA, does provide a protective role from liver damage and NAFLD in subjects, the post-filing art does not provide evidence that any genetic modification of the HSD17B13 gene provides a protective role instead of being a risk factor for chronic liver disease and more importantly, the art at the time of filing does provide evidence of the protective role for a variant of HSD17B13, rs72613567:TA or any genetic modification of the HSD17B13 gene as instantly claimed.
The level of one of ordinary skill:
While the level of one of ordinary skill practicing said invention would be high, the level of predictability is considered variable as evident in the prior art discussed above and is not considered to provide sufficient enablement to practice the claimed invention.
Because the state of the art does not provide evidence of the degree of predictability that causing any type of genetic modification in the HSD17B13 gene which would provide therapeutic or prophylactic effect against a chronic liver disease in a subject, one of ordinary skill in the art would look for guidance or direction in the instant specification.
The level of predictability in the art:
“The “predictability or lack thereof” in the art refers to the ability of one skilled in the art to extrapolate the disclosed or known results to the claimed invention. If one skilled in the art can readily anticipate the effect of a change within the subject matter to which the claimed invention pertains, then there is predictability in the art. On the other hand, if one skilled in the art cannot readily anticipate the effect of a change within the subject matter to which that claimed invention pertains, then there is lack of predictability in the art. Accordingly, what is known in the art provides evidence as to the question of predictability.” (MPEP 2164.03).
The amount of direction provided by the inventor:
The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The “amount of guidance or direction” refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling. >See, e.g., Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1326 (Fed. Cir. 2004).
The existence of working examples:
The working embodiments in the instant application describes associations of HSD17B13 splice variant rs72613567:TA with liver pathology and clinical quantitative traits and diagnoses wherein this was correlated with a lower odds of having chronic liver diseases such as NASH and fibrosis (00489-00490). The working embodiments do not describe methods of using CRISPR/Cas 9 to cause a loss of function of the HSD17B13 gene thereby having a therapeutic or prophylactic effect against the chronic liver disease in a subject who is not a carrier f the HSD17B13 rs72613567 variant.
The standard of an enabling disclosure, at the time of filing, is not the ability to make and test if the invention works but one of the ability to make and use with a reasonable expectation of success. A patent is granted for a completed invention, not the general suggestion of an idea (MPEP 2164.03 and Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1325-26 (Fed. Cir. 2004). The instant invention suggests using a CRISPR/Cas9 system to generate any type of targeted genetic modification in the HSD17B13 gene which would lead to a therapeutic or prophylactic effect against chronic liver diseases in subjects.
While the MPEP 2164.02 states the specification need not contain an example if the invention is otherwise disclosed in such manner that one skilled in the art will be able to practice it without an undue amount of experimentation. In re Borkowski, 422 F.2d 904, 908, 164 USPQ 642, 645 (CCPA 1970), the lack of a working example, however, is a factor to be considered, especially in a case involving an unpredictable and undeveloped art.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure:
The prior art is undeveloped for the role all variants of the HSD17B13 gene plays in providing protection against chronic liver disease or being a risk factor in chronic liver disease. Without further guidance, one of skill in the art would have to practice a substantial amount of trial and error experimentation, an amount considered undue and not routine, to practice the instantly claimed invention.
Maintained Rejections
Claim Rejections - 35 USC § 112
The rejection of Claims 1-15, 17-28, 30, 31 and 35 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph is maintained, because the specification,
while being enabling for
describing associations of HSD17B13 splice variant rs72613567:TA with liver pathology and clinical quantitative traits and diagnoses wherein this was correlated with a lower odds of having chronic liver diseases such as NASH and fibrosis,
expression of HSD17B13 in liver cells and
modification of a mouse HSD17B13 using CRISPR/Cas9
does not reasonably provide enablement for
methods of using CRISPR Cas 9 to generate a targeted genetic modification in the HSD17B13 gene thereby having a therapeutic or prophylactic effect against the chronic liver disease in a subject or
methods of using CRISPR Cas 9 to cause a loss of function of a HSD17B13 splice variant rs72613567:TA thereby having a therapeutic or prophylactic effect against any chronic liver disease in a subject
Response to Arguments
Acknowledgement is made regarding Applicant’s argument but they are not persuasive to overcome the enablement rejection. Applicant presents data showing results of the rs7261357 variant in HSD17B13 and states the data concluded in paragraph [00448] that "[a] loss-of- function variant in HSD17B13 was associated with reduced risk of alcoholic and nonalcoholic liver disease, and progression from steatosis to NASH”. Applicant further argues the present application is not drawn to any type of genetic modification but to a loss of function modification.
In response, the lack of enablement was based on the fact that the prior art or working embodiments do not describe methods of using CRISPR/Cas 9 to target the HSD17B13 gene to generate any genetic modification wherein the method results in a loss of function of the HSD17B13 gene thereby having a therapeutic or prophylactic effect against the chronic liver disease in a subject. The claims are not drawn to a loss of function modification, but to a Cas9 protein that targets a guide RNA target sequence anywhere within the HSD17B13 gene that then results in loss of function of the gene. As claimed, the guide RNA has any sequence that targets any sequence within the HSD17B13 gene and not a loss of function modification.
Applicant argues that the variant mutation discovered is clearly identified as a loss of function variant and further points to a post-filing publication of the inventor that is drawn to the same conclusion. Applicant further points to the post-filing art of Sookoian that found persons who are TA/TA homozygous seem to present natural knockdown of the HSD17B13 active isoforms. Both of these references teach the results are consistent with the HSD17B13 rs72613567 variant that is known to have a loss of function of the gene. Neither of these references provide enablement for methods of generating any targeted genetic modification in the HSD17B13 gene that would result in loss of function which has a therapeutic or prophylactic effect against any chronic liver disease.
Ma et al. (cited previously) found several variants of HSD17B13 that were associated with NAFLD histology and liver enzymes such as rs6834314, rs72613567 or rs62305723 (pages 1508 and 1509). Ma et al. teach that the genetic association of variants in HSD17B13 with features of NAFLD is complex with different SNP’s associated with different phenotypic patterns and only identified two that result in loss of function variants and reduction in NAFLD associated injury and inflammation (see page 1516 last para).
The post filing art of Motomura et al.(cited previously) describes the roles of certain variants of HSD17B13 (as discussed above for references by Abul-Husn et al. and Ma et al.) and confirms the genetic variant rs7261357 of HSD17B13 has a protective effect against NAFLD. The prior or post-filing art does not provide evidence that targeting the HSD17B13 gene to cause any other genetic modification, as broadly claimed, would result in a loss of function and have a therapeutic or prophylactic effect against any chronic liver disease in a subject. Motomura even teach that the genetic variant rs7261357 of HSD17B13, which is known to cause a loss of function, does not correlate with viral hepatitis, another type of a chronic liver disease (see page 7, 3.2). Motomura concludes the protective role of these newly discovered genetic variants of HSD17B13 needs further study (conclusion page 9).
Therefore, the prior art demonstrates that the newly discovered genetic variants of HSD17B13 may not have a protective role such that it would have a therapeutic or prophylactic effect against any chronic liver diseases and thus does not provide enablement for any targeted genetic mutations of HSD17B13 that causes a loss of function that results in a therapeutic or prophylactic effect on against any chronic liver disease.
The standard of an enabling disclosure, at the time of filing, is not the ability to make and test if the invention works but one of the ability to make and use with a reasonable expectation of success. A patent is granted for a completed invention, not the general suggestion of an idea (MPEP 2164.03 and Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1325-26 (Fed. Cir. 2004). The instant invention suggests using a CRISPR/Cas9 system to generate any type of targeted genetic modification in the HSD17B13 gene which would then result n a loss of function and a therapeutic or prophylactic effect against chronic liver diseases in subjects.
The rejection is therefore maintained.
Double Patenting
Acknowledgement is made of Applicant's request that the rejection be held in abeyance until allowable matter is indicted in the instant claims, therefore the rejection of claims 1-15, 17-28, 30, 31 and 35 under the judicially created doctrine of obviousness-type double patenting as being unpatentable over claims 1-35 are rejected under the judicially created doctrine of obviousness-type double patenting as being unpatentable over claims 1-40 of U.S. Patent No. 11,485,958.
Conclusion
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 extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action. Any inquiry concerning this communication or earlier communications from the examiner should be directed to KIMBERLY CHONG at (571)272-3111. The examiner can normally be reached Monday thru Friday 9-5 pm.
If attempts to reach the examiner by telephone are unsuccessful please contact the SPE for 1636 Neil Hammell at 571-270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KIMBERLY CHONG/Primary Examiner, Art Unit 1636
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