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 .
Election/Restrictions
Applicant’s election with traverse of Group IV (Claims 14-21; drawn to a method for treating an inflammatory disease or iron transport dysregulation resulting from inflammation by modifying a cell of the individual by inserting an exogenous TRF2 gene into the individual's genome) in the reply filed on August 27, 2025, is acknowledged.
Claims 1-13 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention (Groups I-III), there being no allowable generic or linking claim.
Response to Arguments
Applicant's arguments filed August 27, 2025, are acknowledged.
Applicant argues that the claims of Group I encompass related concepts and that search efforts would be largely duplicative and would, therefore, not represent an excessive prosecutorial burden (page 1)
Applicant's arguments have been fully considered but they are not persuasive.
The restriction was not predicated on US practice (i. e. search burden). The application was filed under 371 practice so the criteria for restriction is lack of unity. The previous restriction, mailed July 29, 2025, recited the reasons for lack of unity.
DETAILED ACTION
The amended claims filed on August 27, 2025, have been acknowledged. In light of the Applicant’s elected invention, claims 1-13 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 14-21 are pending and examined on the merits.
Continuation Application Contains New Matter Relative to the Prior-Filed Application
Applicant states that this application is a continuation application of the prior-filed application. A continuation application cannot include new matter. Applicant is required to delete the benefit claim or change the relationship (continuation) to continuation-in-part because this application contains the following matter not disclosed in the prior-filed application: Claim 21 and paragraphs 0058-0063 contain information about modulating superoxide dismutase or a calcium transport protein that were not in the prior filed application (17/708,911).
Claim Objections
Claims 14 and 16-19 are objected to because of the following informalities:
Claims 14 and 16-19 us the abbreviation “TRF2”, which has not been spelled out upon first use. Although claims are allowed abbreviations, if an abbreviation is not spelled out upon first use in a claim, MPEP §2429 states that Applicant only use abbreviations that are specifically defined in "WIPO Standard ST.25 (1998)" or that are well known and would be clear to someone who had not read the invention description. As a related matter, claims 14 and 16-19, use the abbreviation TRF2, however, this is the incorrect abbreviation for transferrin receptor 2 as identified in the specification in paragraph 0012. Instead, the abbreviation should be TFR2.
Appropriate correction is required.
Specification
The disclosure is objected to because of the following informalities:
The specification uses two different abbreviations throughout for transferrin receptor 2, TFR2 and TRF2. The specification should be fixed to use the appropriate abbreviation, TFR2, throughout.
Appropriate correction is required.
Priority
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, 365(c), or 386(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. 119(e) 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 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. 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, Application No. 17/708,911, filed March 30, 2022, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. This application does not provide information related to modulating SOD or a calcium transport protein of the cell. However, Application No. 18/739,865, filed on June 11, 2024, did provide the above information. Therefore, claims 14-20 receive domestic benefit from US application 17/708,911, filed on March 30, 2022.
Information Disclosure Statement
The information disclosure statement (IDS) filed on June 11, 2024, has been considered.
Claim Rejections - 35 USC § 112
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.
Claim 21 is 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 21 recites the limitation “modulation of a superoxide dismutase (SOD) or a calcium transport protein of the cell.” Claim 21 only states a result (modulation of superoxide dismutase or calcium transport protein) without identifying any structure capable of achieving this result nor any functional features of the modulation. It is not clear what is meant by modulating the proteins as there are multiple possible interpretations for achieving this result. For example, modulation could refer to changing the number of proteins in the cell by either increasing or decreasing the protein levels (this is what is discussed in the specification in paragraphs 0058-62) or through modulating the protein itself such as through an inhibitor (this is what is discussed in the specification in paragraph 0063 using calcium channel blockers).
Thus, one of ordinary skill in the art would not know from the term modulation what structure or steps are encompassed by the claim.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 14-16 and 18-19 are rejected under 35 U.S.C. 103 as being unpatentable over Gao et al. (Blood 115: 3374-3381. 2010; previous art of record), Wang et al. (Hematologica 105: 2071-2082. 2020), and Nash et al. (J Gene Med 6: 974-983. 2004).
Regarding claim 14, Gao teaches a method for treating an iron transport disease (hereditary hemochromatosis) which causes increased intestinal iron absorption and hepatic iron overload and can lead to inflammatory diseases, such as diabetes and arthritis. Gao teaches that Type 3 hereditary hemochromatosis is caused by a variety of missense and nonsense mutations in TfR2. The most common mutation is the nonsense mutation (Y250X), which results in a truncation of TfR2 at amino acid 250. The equivalent mutation in the mouse is Y245x (i.e. identifying an individual in need of treatment). The treatment involves using a recombinant adeno-associated virus, AAV2/8 virus that encodes mouse Tfr2 (i.e. exogenous TfR2 gene), for hepatocyte-specific expression of Tfr2 in mice. Expression of Tfr2 in Tfr2-deficient mice increased hepcidin mRNA and lowered hepatic iron and transferrin saturation (page 3374, column 1, paragraph 1-page 3376, column 2, paragraph 2, and abstract).
Gao does not teach wherein they inserted the exogenous TfR2 gene into the individual’s genome.
However, Nash teaches that they generated transferrin receptor 1 (Tfr1)-deficient hematopoietic stem cells (HSCs) (conditional knockout) which caused multiple defects in hematopoiesis, including the colony-forming capacity of the HSCs. Nash teaches that they infected the Tfr1-deficient HSPCs from the fetal liver (FL) with a lentivirus encoding the wild-type Tfr1 gene and that the wild-type gene rescued the colony-forming capacity of the HSPCs (page 2071, paragraph 1-page 2079, column 2, paragraph 1 and Figure 7).
Nash teaches that lentiviral vectors enter and integrate their transgene permanently into predominantly quiescent target cells. Furthermore, they are non-toxic and nonimmunogenic making them ideal gene delivery vectors for liver-directed gene therapeutic approaches. Furthermore, Nash teaches that the lentiviral vectors can be combined with an HBV surface promoter and HBV enhancer element to achieve increased specificity for hepatocytes (page 975, column 1, paragraph 5 and abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the AAV vector backbone used by Gao with a lentiviral vector backbone, as identified by Wang, to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to substitute with a reasonable expectation of success because Wang successfully reduces to practice that a lentivirus encoding Tfr1 can rescue HSPC colony-forming capacity and Gao teaches that Tfr2 is a known homolog of Tfr1 (page 3374, column 2, paragraph 1). Therefore, one of ordinary skill in the art would understand that a lentivirus encoding Tfr2 would also successfully integrate into cells and express the Tfr2 gene. Furthermore, Nash teaches that lentiviral vectors enter and integrate their transgene permanently into predominantly quiescent target cells. Furthermore, they are non-toxic and nonimmunogenic making them ideal gene delivery vectors for liver-directed gene therapeutic approaches. Therefore, it would have been obvious that a lentiviral vector backbone could be used instead of an AAV vector backbone as this would lead to permanent expression in the cell versus episomal expression from the AAV vector. As the disorder being treated is a genetic disorder, it would make sense to want to achieve permanent expression of the Tfr2 gene to improve symptoms long term and to limit the need for repeated administrations as would be required with AAV vectors. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claims 15-16, Gao teaches that their method can be used to treat a point mutation that causes a nonsense mutation (Y250X in humans, Y245x in mice) (page 3374, column 1, paragraph 1-page 3376, column 2, paragraph 2, and abstract). As the mutation alters the amino acid residue 250/245 to a nonsense mutation, this mutation occurs in a structural region.
Regarding claim 18, lentiviruses are a type of retrovirus.
Regarding claim 19, the combined teachings of Gao, Wang, and Nash do not teach wherein the cell is further modified by introducing TFR2 protein.
However, it would have been obvious that one could administer TFR2 to a cell in combination with the lentiviral vector encoding TFR2. It is well understood in the art that the lentiviral vector integration of the exogenous gene and the eventual expression takes time whereas administering TFR2 proteins would allow for the cells to use these proteins to begin modulating iron levels in advance of expression of the integrated exogenous TFR2. Therefore, it would have been obvious to co-administer the lentivirus encoding TFR2 with TFR2 proteins to achieve earlier changes in iron levels than would occur with lentiviral administration alone.
Claims 14 and 16-17 are rejected under 35 U.S.C. 103 as being unpatentable over Gao et al. (Blood 115: 3374-3381. 2010), Wang et al. (Hematologica 105: 2071-2082. 2020), and Nash et al. (J Gene Med 6: 974-983. 2004), as applied to claim 14 above and further in view of Roetto et al. (Blood 115: 3382-3389. 2010; previous art of record).
The teachings of Gao, Wang, and Nash are as discussed above.
The combined teachings of Gao, Wang, and Nash do not teach wherein the mutation occurs in a regulatory portion of the TFR2 gene.
However, Roetto teaches that they generated a different Tfr2 knockout mouse wherein they used Cre-Lox recombination to remove exons 4-6 (i.e. a deletion) and the corresponding introns and splice donor and acceptor sites (i.e. regulatory elements) (Figure 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention that one could use the TFR2 encoding lentiviral vector of the combined teachings of Gao, Wang, and Nash to treat other mutations, such as the large TFR2 deletion of Roetto, to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to target other TFR2 knockout mutants with a reasonable expectation of success because the lentiviral vector encoding the TFR2 would also rescue wild-type TFR2 expression in the knockout mutants of Roetto and restore TFR2 expression in the cell to rescue the wild-type phenotype for iron transport/metabolism. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Claims 14 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Gao et al. (Blood 115: 3374-3381. 2010), Wang et al. (Hematologica 105: 2071-2082. 2020), and Nash et al. (J Gene Med 6: 974-983. 2004), as applied to claim 14 above and further in view of Loreal et al. (Pharmaceuticals 11: 1-14. 2018).
The teachings of Gao, Wang, and Nash are as discussed above.
The combined teachings of Gao, Wang, and Nash do not teach wherein the method further comprises supplemental iron removal.
Loreal teaches that iron depletion treatments are commonly used as a treatment for hemochromatosis to prevent severe complications from occurring (page 5, paragraph 5-page 8, paragraph 3).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of treating hemochromatosis of the combined teachings of Gao, Wang, and Nash by including an iron depletion step, as identified by Loreal, to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because Loreal teaches that iron depletion treatments are commonly used as a treatment for hemochromatosis to prevent severe complications from occurring. Therefore, it would have been obvious to perform iron depletion at the start of the therapy to remove excess iron from the system before the exogenous TFR2 is able to integrate and begin expression and effectuate iron transport and metabolism. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Claims 14 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Gao et al. (Blood 115: 3374-3381. 2010), Wang et al. (Hematologica 105: 2071-2082. 2020), and Nash et al. (J Gene Med 6: 974-983. 2004), as applied to claim 14 above and further in view of Valenti et al. (Med Genet 41:946–950. 2004).
The teachings of Gao, Wang, and Nash are as discussed above.
The combined teachings of Gao, Wang, and Nash do not teach wherein the method further comprises modulating superoxide dismutase. As per the 112b above, modulating superoxide dismutase is interpreted to mean modulating superoxide dismutase (SOD) protein levels.
Valenti teaches that assessed whether a genetic variant of SOD, affecting detoxification of reactive oxygen species, influences iron induced tissue damage in patients with hereditary hemochromatosis. Mutations in this gene previously linked to impaired enzymatic activity, is strongly associated with the presence of cardiomyopathy.
Furthermore, iron toxicity is mediated by oxidative damage, which results in mitochondrial injury. Manganese mitochondrial superoxide dismutase (MnSOD or SOD2) catalyses the removal of superoxide at its site of production, the matrix side of the inner mitochondrial membrane. Increased iron concentration induces MnSOD expression, and overexpression of MnSOD prevents iron related oxidative damage (page 946, column 1, paragraph 1-column 2, paragraph 2, page 948, column 1, paragraph 2-column 2, paragraph 1, and abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of treating hemochromatosis of the combined teachings of Gao, Wang, and Nash by including a step of modulating SOD expression levels, as identified by Valenti, to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because Valenti teaches that SOD mutations have been found in patients with hereditary hemochromatosis and that overexpression of MnSOD prevents iron related oxidative damage. Therefore, it would have been obvious to increase SOD protein levels to prevent iron related oxidative damage until the exogenous TFR2 is expressed in sufficient numbers to normalize the iron levels. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KEENAN A BATES whose telephone number is (571)270-0727. The examiner can normally be reached M-F 7:30-5:00.
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, Doug Schultz can be reached at (571) 272-0763. 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.
/KEENAN A BATES/Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631