Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions based on the effective filing date of 05/16/2011.
DETAILED ACTION
The text of those sections of Title 35, U.S. Code not included in this action can be found
in a prior Office action.
This Action is in response to the papers filed on November 21, 2025. Pursuant to the amendment filed on November 21, 2025, claims 70,74, 77, 78, 82, 85-92 are currently pending of which claims 70, 70,74, 77, 78, 82 have been amended. Claims 72, 73, 75, 76, 80, 81, 83, and 84 have been cancelled. No new claims have been added.
The restriction requirement between Groups I-II was previously made FINAL in the Office Action dated October 23, 2024 wherein claims 85-92 were previously withdrawn.
The terminal disclaimers filed on 01/13/2025 and disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of the full statutory term of U.S. Patent Nos. 9,820,475, 10,080,353, 10,405,526, 11,019,809, and U.S. Patent Application No. 17/242,963 have been reviewed and are accepted. The terminal disclaimers have been recorded.
Therefore, claims 70, 74, 77, 78, and 82 are currently under examination to which the following grounds of rejection are applicable.
Response to Arguments
Withdrawn Objections/Rejections in response to Applicants’ arguments or amendments:
Claim Objections
In view of Applicants' amendment to the claims dated November 21, 2025, wherein claim 70 has been amended, the objection to claim 70 has been withdrawn.
Maintained Objections/Rejections in response to Applicants’ arguments or amendments:
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 70, 74, 77, 78, and 82 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:
A modified swine wherein at least one allele of a CD163 gene has been modified by introducing a deletion into the CD163 gene within exon 7, wherein the modified CD163 gene results in an alteration of scavenger receptor cysteine-rich 5 (SRCR5) domain of a CD163 protein, and wherein the altered extracellular domain of the CD163 protein results in reduced or eliminated uptake of a porcine reproductive and respiratory syndrome virus (PRRSV) by loss of interaction of the altered extracellular domain of the CD163 protein to the PRRSV.
is not enabled in view of the recited claims filed on November 21, 2025, wherein there is no connection between the modification of the CD163 via deletion with the alteration observed in the SRCR5 domain of the translated CD163 protein. Furthermore, claim 77 has not been amended to match claim 70 in stating the modification is by the introduction of a deletion, such that the deletion occurs in exon 7.
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 use the invention commensurate in scope with these claims.
In determining whether Applicant’s claims are enabled, it must be found that one of skill in the art at the time of invention by applicant would not have had to perform “undue experimentation” to make and/or use the invention claimed. Such a determination is not a simple factual consideration, but is a conclusion reached by weighing at least eight factors as set forth in In re Wands, 858 F.2d at 737, 8 USPQ 1400, 2d at 1404. Such factors are: (1) The breadth of the claims; (2) The nature of the invention; (3) The state of the art; (4) The level of one of ordinary skill in the art; (5) The level of predictability in the art; (6) The amount of direction and guidance provided by Applicant; (7) The existence of working examples; and (8) The quantity of experimentation needed to make and/or use the invention.
The office has analyzed the specification in direct accordance to the factors outlines in In re Wands. MPEP 2164.04 states: “[W]hile the analysis and conclusion of a lack of enablement are based on factors discussed in MPEP 2164.01(a) and the evidence as whole, it is not necessary to discuss each factor in written enablement rejection.” These factors will be analyzed, in turn, to demonstrate that one of ordinary skill in the art would have had to perform “undue experimentation” to make and/or use the invention and therefore, applicant’s claims are not enabled.
Claims 70 is directed to a modified swine wherein at least one allele of a CD163 gene has been modified by introducing a deletion into the CD163 gene, wherein the modified CD163 gene results in an alteration of scavenger receptor cysteine-rich 5 (SRCR5) domain of a CD163 protein, and wherein the altered extracellular domain of the CD163 protein results in reduced or eliminated uptake of a porcine reproductive and respiratory syndrome virus (PRRSV) by loss of interaction of the altered extracellular domain of the CD163 protein to the PRRSV.
Claim 77 is directed to a modified swine wherein at least one allele of a CD163 gene has been modified, and wherein the modified CD163 gene result in an alteration of at least one extracellular domain of a CD163 protein, wherein the altered extracellular domain is comprised of scavenger receptor cysteine-rich 5 (SRCR5) domains, and wherein the altered extracellular domain results in reduced or eliminated uptake of a porcine reproductive and respiratory syndrome virus (PRRSV) by loss of interaction of the altered extracellular domain of the CD163 protein to the PRRSV, produced by a method comprising: enucleating a swine oocyte; fusing the oocyte with a donor swine cell, the genome of the donor swine cell comprising a deletion, an insertion, and combinations thereof in at least one allele of the CD163 gene, wherein the modified CD 163 gene result in an alteration of at least one extracellular domain of a CD163 protein; and activating the oocyte to produce an embryo.
The claims that are dependent upon these claims further specify the locations as to where the alteration occurs, i.e. exon 7 of the CD163 gene.
(1) Quantity of experimentation needed: There is considerable experimentation required to determine which locations in the CD163 gene are deleted wherein the SRCR5 domain is then altered while maintaining the functional properties of the remaining domains, and maintaining viability of the modified swine, in addition to outcomes related to reduced or eliminated uptake of a porcine reproductive and respiratory syndrome virus (PRRSV) by loss of interaction of the altered extracellular domain of the CD163 protein.
This would require building numerous constructs for such alterations to occur in a swine after successful transformations into a donor swine cell, which is then followed by the downstream steps of somatic nuclear transfer to obtain a modified swine or embryo. There is no certainty that a truncated CD163 is viable for the organism despite there being a loss of interaction of CD163 and PRRSV. Additionally, there is no clarity if any or all of these claimed alterations would result in loss of interaction of CD163 and PRRSV. Lastly, a clear connection is required between the site of the CD163 deletion and the alteration of the SRCR5 domain in order to determine the extent of this alteration. For example, the deletion may encompass other SRCR domains, for which are not enabled by the instant Specification.
In reference to the type of alterations it would require undue experimentation to obtain different forms of alterations based on using different genomic editing machinery encoded constructs. For example, it may be more challenging to obtain a substitution of genomic region as opposed to a small deletion that can occur with different nucleases. The claims, as currently listed, are directed to deletions, which is known to encompass repair by homologous recombination or non-homologous end-joining, both of which would have different outcomes on the structural, and functional characteristics of the claimed CD163 gene. The Specification only supports in view of Example 2 and the Drawings, the substitution of SRCR5 with SRCR8 of CD163L. Despite, CD163 domains being known, site-specific nucleases and corresponding techniques being well-known, there remains undue experimentation on altering the different domains CD163 for different editing outcomes in view of the functional outcomes with PRRSV in a viable swine or swine embryo. Specifically, the claim recites a deletion in CD163 gene, but it is unclear where this deletion is located in the allele that would cause alteration in the SRCR5 domain of the CD163 protein.
(2) Amount or direction or guidance presented & (3) the presence or absence of working examples: The specification describes in Example 1 the modification of the SIGLEC1 gene in swine, and the corresponding steps to obtain a modified swine, stating “The approach employed to ablate the sialoadhesin gene made use of homologous recombination to remove protein coding exons and introduce premature stops in the remaining coding sequence of the sialoadhesin gene… In the current gene disruption, part of exon 1 and all of exons 2 and 3 were replaced with a neomycin selectable cassette by using a replacement-type vector (panel D of Fig.1)” (par 0081, 0082). The Example then describes steps for somatic cell nuclear transfer, surrogate preparation, embryo transfer, pregnancy diagnosis and then delivery. The born modified swine, specifically males, were screened for the SIGLEC1 inactivation, and then crossed with females to obtain a homozygous animal for the alteration. It is important to note that these steps are directed to a different gene than what is being claimed in the instant invention.
Example 2 describes the generation of a CD163 targeting construct for which the SRCR5 domain of CD163 is swapped out with the SRCR domain CD163L. This was done because it was already established that the deletion of the cytoplasmic domain of CD163 eliminates infectivity of PRRSV, as does the deletion or modification of SRCR domain 5. Furthermore, some of the SRCR domains of CD 163 have important functions for survival of the animal, e.g. hemoglobin removal, modification of the gene such that these other functions remain intact represents a solid strategy to create pigs that are resistant to PRRSV., and lastly, prior research has also suggested that the replacement of SRCR5 domain with CD163L domain 8 also blocks infectivity (par 0093; Fig. 5, 6). Example 2 which is directed to the instant claims can be seen as representing a subset of the modified swine encompassed by claims 70 and 77. Despite the steps of obtaining a modified swine being known, as was shown with SIGLEC1 this is not enabling for all the alterations and corresponding outcomes encompassed by these claims. As described above, the respective exon(s) that comprise deletions in relation to SRCR5 needs to be recited.
(4) Nature of the invention & (8) the breadth of the claims:
The claims are directed to a modified swine wherein the CD163 allele has been modified (claim 77), and more specifically comprising a deletion (claim 70), wherein the translated CD163 has an altered SRCR5 domain. Claim 77 further recites product-by-process limitations in obtaining the modified swine.
(5) State of the prior art: The Background of the Invention Section of the Specification describes CD163 as “CD163 has 17 exons and the protein is composed of an extracellular region with 9 scavenger receptor cysteine-rich (SRCR) domains, a transmembrane segment, and a short cytoplasmic tail. Several different variants result from differential splicing of a single gene (Ritter et al. 1999a; Ritter et al. 1999b). Much of this variation is accounted for by the length of the cytoplasmic tail.” (par 0011)
Furthermore, “CD163 has a number of important functions, including acting as a haptoglobin-hemoglobin scavenger receptor. Elimination of free hemoglobin in the blood is an important function of CD163 as the heme group can be very toxic (Kristiansen et al. 2001). CD163 has a cytoplasmic tail that facilitates endocytosis. Mutation of this tail results in decreased haptoglobin-hemoglobin complex uptake (Nielsen et al. 2006). Other functions of CD163 include erythroblast adhesion (SRCR2), being a TWEAK receptor (SRCRI-4 & 6-9), a bacterial receptor (SRCR5), an African Swine Virus receptor (Sanchez-Torres et al. 2003), and a potential role as an immune-modulator (discussed in (Van Gorp et al. 2010a))” (0012). Lastly, “Prior research has also suggested that the replacement of SRCR5 domain with CD163L domain 8 also blocks infectivity (Van Gorp et al. 2010b). Thus, a targeting construct can be designed as shown in Figure 6 to swap out SRCR5 of CD 163 with the SRCR domain CD 163L (0093). These citations are taken from the cited paragraphs of the Specification provided by the Applicant.
Altogether the cited art by Applicant points to the connection between SRCR5 with PRRSV infection, but does not describe truncation by an early stop codon, but rather swapping or substitution of the specific SRCR5 domain with another SRCR domain wherein the remaining domains are still present. Moreover, it remains unclear how the alteration in SRCR5 is connected to the modification of CD163, or more specifically the deletion therein.
(6) Relative skill of those in the art: The level of skill in the art is high.
(7) Predictability or unpredictability of the art: There remains a high unpredictability due to the majority of research, as listed above, describing which domains are necessary for infection, but this does not account for truncated versions of the protein and the role it has on resistance, and potentially survival of the animal. Van Gorp et al. 2009 (Journal of virology 84.6 (2010): 3101-3105., as cited by Applicant) describes in Fig 2 the swapping of domains/regions of CD163 necessary for PRRSV infection, but the art remains unpredictable for whole deletions or region(s).
Based on this analysis, the specification does not provide an enabling disclosure for the alterations described in claims 70 and 77, as the Specification describes the deletion of SRCR or modification thereof results in increased resistance, and therefore, the deletion in the CD163 needs to be recited. Altogether, it would require undue experimentation to determine the potential improved resistance that could be obtained from these claimed alterations to CD163.
The Examiner acknowledges the amendment to claim 70 and 77 to overcome the 35 U.S.C. 112(a) rejection for a lack of a written description in view of the amendments stating, “by loss of interaction of the altered extracellular domain of the CD163 protein to the PRRSV”. Additonally, the examiner acknowledges the amendments made in view of the last Office Action, wherein the swine is now recited as modified, the SRCR domain is limited to the SRCR5 domain, and stating the modification as being a deletion in the CD163 gene. However, claim 77 has not been amended to recite this modification, and moreover the location of the modification in the CD163 has not been recited to clarify the “alteration” of the SRCR5 recited. The instant claims should appropriately recite the location in the CD163 gene, which appears to be exon 7 based on dependent claims 74 and 82. The examiner concedes that “(3) wherein the alteration is a substitution of SRCR5 with SRCR domain 8 from CD163 Ligand (CD163L)” need not be claimed as stated in the previous rejection, in view of the Specification stating the SRCR5 domain can be deleted for improved resistance (par 0093). Therefore, the rejection is maintained.
New Grounds of Rejection
Claim Objections
Claim 77 is objected to because of the following informalities:
Regarding claim 77 in line 4, the single SRCR5 domain is listed in the plurality, when it should be singular since there is only one SRCR5 domain per allele.
Appropriate corrections are required.
Examiner’s Comment
It is noted that claims 74 and 82 recite “wherein the at least one modified CD163 allele is exon 7”, yet this is unclear as it appears it should be describing that the modification is at exon 7 of the modified allele. In particular, the claims are confusing alleles with exons.
Conclusion
Claims 70, 74, 77, 78, and 82 are rejected. No claims are allowed.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MICHAEL A RIGA whose telephone number is (571)270-0984. The examiner can normally be reached Monday-Friday (8AM-6PM).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maria G Leavitt can be reached at (571) 272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MICHAEL ANGELO RIGA/Examiner, Art Unit 1634
/TERESA E KNIGHT/Primary Examiner, Art Unit 1634