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 .
Election/Restrictions
Applicant’s species election of SEQ ID NO.31, with traverse, in the reply filed on 17 Aug 2026 is acknowledged.
Applicant traverses on grounds that the structural motif of SEQ ID NO.167 is conserved and present in 13 different proteins identified as SEQ ID NO.31, 33, 35, 37, 47, 49, 51, 53, 55, & 57. Applicant argues that presence of a shared sequence or motif indicates a species election requirement is improper.
However, this is not persuasive for purposes of rejoinder prior to examination, as each of these 13 different proteins is a distinct molecule merely comprising a shared motif (SEQ ID NO.167). These are identified via database comparison, and review of the specification shows there is no functional description or validation of whether the claimed sequences have the same biological activity in planta.
The presence of a single conserved structural motif does not outweigh that different molecules, absent functional description, need to be regarded as distinct species for purposes of examination. Further, as claimed, each of these sequences is recited using open language and simultaneously claims variants of as little as 90% identity. Therefore, examination of the additional, distinct 12 sequences not elected, and all their potential variants of only 90% identity would require search of an extensive array of distinct molecules.
Claim Status
Claims 17, 24, 26 and 47-48 are under examination on the merits.
Claims 1, 4, 8, 11, 14, 27-28, 33, 46 and 50-55 are withdrawn as non-elected matter.
Claims 2-3, 5-7, 9-10, 12-13, 15-16, 18-23, 25, 29-32, 34-45, 49 are canceled.
Priority
Foreign priority is claimed to CHINA PCT/CN2019/104566.
Claims 17, 24, 26 and 47-48 receive the U.S. effective filing date of 05 Sep 2019.
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 17, 24, 26, and 47-48 are 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 claims contain 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.
Regarding the breadth of mutations described.
The claims are broadly drawn to a genetically altered plant that comprises a mutation in an amino acid permease (AAP) protein having at least one (but unspecified maximum) number of mutations in the sequence at a position in a motif of SEQ ID NO:167, wherein the plant is characterized by increased expression or activity of the polypeptide, wherein the plant produces larger and heavier seeds, and wherein the plant is not Arabidopsis.
Referring to the specification for description of the process of mutating AAP, Applicant describes a naturally occurring loss-of-function mutant allele of AAP8 which reduces seed size [Specification, p.2, l.20-31]. They also describe the sequence of the wild-type AAP8 allele which functions correctly and results in larger seeds [id].
The only directed manipulation of AAP8 described is the transgenic complementation (i.e. regular expression) of the mutant allele with vectors carrying the functional WT allele [Specification, p.3, l.1-16; p.36, l.14-24]. Applicant references that other mutations could in theory be made to AAP8 that would impact its expression, but no examples are provided indicating Applicant has tested or verified any other form of modifying AAP8 beyond genomic complementation testing [‘Examples’ p.23, l.25—p.40, l.25]. Applicant provides no example of mutation or manipulation other than use of the WT allele and further indicates that there are no dosage effects (i.e. increasing copy number of the non-functional allele does not further increase seed size) [p.36, l.14-24].
As such, it does not appear Applicant is in possession of any form of mutating or altering AAP8 that functionally impacts seed size beyond that of restoring loss-of-function phenotypes to WT with correspondingly normal seed size.
Regarding possession in any and all non-Arabidopsis plant species.
The specification defines the term “genetically altered” as encompassing plants which are altered compared to the naturally occurring wild type (WT) plant, including those which are gene edited or transgenic [p.10 l.33 – p.11, l.10]. Broadest reasonable interpretation of such a claim is that any alteration compared to WT forms of this allele is encompassed in any and all plants. This would include all naturally occurring allelic forms or orthologs varying from WT that confer seed size differences.
To this effect, the specification describes a single allele in the Arabidopsis thaliana AAP8 protein which increases its activity and results in larger seeds via valine to alanine substitution at position 410 of SEQ ID NO:1 [p.39, l.17-27; Figures 8, 11]. Applicant does not describe use or effects of the AAP8 protein and/or its manipulation in any other plant than Arabidopsis [Specification, p.42, l.11-12].
Applicant indicates DNA sequences similar to Arabidopsis AAP8 identified in silico through comparison among genomic databases, however, they do not move beyond pointing to potential orthologs in the returned database search results. There is no testing, validation, or any type of description of how the potential orthologous sequences work in any plant species other than Arabidopsis. It is not known if the identified sequences alone or mutated in the ways described by Applicant are capable of altering seed size in their respective plant species. Research reports directed to AAPs indicates that even within a species these exist as functionally divergent homologs, and thus would necessitate such functional validation [see p.15, col.1, ¶3—col.2, par.1; p.17, col.2, ¶3—p.18, col.1, ¶.2 in Zhou et al. BMC Plant Biology (2020) 20:151; Pub. 8 Apr 2020].
An example of a single amino acid substitution which increases the activity of a single AAP8 protein in Arabidopsis does not provide an understanding of the relevance of related sequences in any and all plants. The specification fails to make up for this lack of knowledge on the art at filing. This is particularly notable in the instant Application, as claim 17 specifically requires that such plants with altered AAP8 and seed size are not Arabidopsis. Thus, the entire description is based on the one genus of organisms excluded by claims and does not describe any other plants.
Regarding any and all protein variants of AAP8.
The specification describes a single allele in the Arabidopsis thaliana AAP8 protein which confers an increased activity and results in larger seeds — a valine to alanine substitution at position 410 of SEQ ID NO:1 [p.39, l.17-27; Figures 8, 11]. Thus, the specification does not describe species within the full scope of the claimed AAP (or AAP8) proteins and thus does not describe a representative number of species within the claimed genus of plants which have increased activity of an AAP (or AAP8) polypeptide or increased activity of a homolog of an AAP (or AAP8) polypeptide.
The specification broadly describes that AAP8 proteins comprise an “Aa_trans” motif which is characteristic of amino acid transporter proteins; the length of this generally described domain is nearly the entire length of the AAP8 protein [Figure 3; Page 7 l.9-27; SEQ ID NO: 168]. Similar to the reports published prior to the filing date of the instant invention, the specification describes that plants having loss of function mutations in AAP8 had reduced seed yield and increased seed abortion [p.37, l.25 – p.38, l.2; Figure 3].
The specification describes only one specific substitution, which is just a single allele, related to an increase in function in AAP8 protein, corresponding to a valine to alanine substitution at position 410 of SEQ ID NO:1 [p.39 l.17-27; Figures 8, 11]. This is described in a single model plant species, Arabidopsis. The specification also provides the corresponding position of this substitution in other amino acid permease proteins (Figure 12).
However, it is not known if such a substitution would confer the function of increasing the activity of any possible AAP protein. Furthermore, this example of a single amino acid substitution which increases the activity of a single AAP8 protein does not provide an understanding of the common structural and functional features of all AAP (including all AAP8) proteins which may have increased function, nor their relevance in other plants. Research reports directed to AAPs indicates that even within a species these exist as functionally divergent homologs, and thus would necessitate such functional validation [see p.15, col.1, ¶3—col.2, par.1; p.17, col.2, ¶3—p.18, col.1, ¶.2 in Zhou et al. BMC Plant Biology (2020) 20:151; Pub. 8 Apr 2020].
There is no description in the specification of how the structure of AAPs generally (including AAP8) relates to the structure of unspecified species-specific variants of AAP (or AAP8) which may have increased activity. No motifs or domains that are necessary and sufficient structural elements to confer increased activity to an AAP (or AAP8) protein are described in the specification. As extensively described in the Office action mailed 06/03/2024, the structure-function relationship of AAP8 proteins with increased activity was not established in the art after the time of filing.
Describing and reducing to practice the claimed genus of amino acid substitutions in which there is any mutation at any unspecified position in the motif presented by SEQ ID NO.167 is unpredictable. While it is known that many amino acid substitutions, additions or deletions are generally possible in any given protein, the positions within the protein’s sequence where such amino acid changes can be made with a reasonable expectation of success (without altering protein function) are limited. Certain positions in the sequence are critical to the protein’s structure/function relationship, for example various sites or regions directly involved in binding, activity, and in providing the correct three-dimensional spatial orientation of binding and active sites. These regions can tolerate only relatively conservative substitutions or no substitutions at all [see Abstract & p.1043-1044 in Keskin (2004) Protein Science 13: 1043-1055, and, Abstract; p.9206; Table 1 in Guo (2004) PNAS USA 101: 9205-9210.]
Applicant has not reduced to practice a representative number of the broadly claimed genus of claimed protein sequences. The Applicant fails to describe structural or functional features common to the genus of broadly claimed polypeptides allegedly responsible for the recited function(s), e.g., how exactly the myriad of possible molecules are causally related to the recited increase in expression and/or activity of the AAP protein, and in all plants, plant parts, and plant cells.
Given Applicant has provided very vague description of the method steps or structures that would link the expression of (i) unspecified mutations in the AAP polypeptide, with the recited increase in expression and/or activity of the AAP protein, resulting in larger and heavier seeds, it remains unclear what features or method steps are capable of performing the claimed function. Applicant also limits their description to use in one genus, Arabidopsis, and provides no other description for use of the sequence motifs in any other plant, or plants generally.
As such, the Specification fails to provide adequate written description to support the breadth of the claims. Therefore, one skilled in the art would not have recognized Applicant to be in possession of the claimed invention when the application was filed.
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.
Claims 17, 24 & 26 are rejected under 35 U.S.C. 103 as being unpatentable over Perchlik [Plant Physiology, September 2017, Vol. 175, pp. 235–247; Pub. 21 July 2017], in view of Santiago [Plant Physiology, May 2016, Vol. 171, pp. 508–521; Pub. 25 March 2016] and Zhang [Nature Scientific Reports 7: 5053; Pub. 11 July 2017].
Perchlik teaches the improvement of plant nitrogen use efficiency and the production of higher seed yields (i.e. greater source-to-sink amino acid transport) via transgenic overexpression of amino acid transport proteins [p.237, col.1, ¶.2—p.239, col.1, ¶.1; p.241, col.1, ¶.2—p.242, col.1, ¶.1; p.244, col.2, ¶.2; p.245, col.1, ¶.5]. They teach that overexpression of the AAP1 gene leads to increased transport and phloem-loading of amino acids with increased seed yield (i.e. increased activity of the AAP polypeptide) [p.241, col.1, ¶.2—p.242, col.1, ¶.1]. They teach the production of legume crop plants (i.e. non-Arabidopsis) overexpressing the AAP1 gene and their characterization under variable nitrogen conditions [p.244, col.2, ¶.2].
Perchlik does not teach mutation of, or overexpression of, the AAP8 protein, its functional motifs (i.e. SEQ ID NO.167), or its orthologs (i.e. SEQ ID NO.31). Perchlik does not teach the functional relationship among AAP proteins, or sequence relationships between AAP1 and AAP8. Perchlik does not teach Glycine max AAP8 or its involvement in protein storage or seed formation.
Santiago teaches that in addition to AAP1, other proteins in the AAP family are involved in source-sink dynamics and transport of nutrients into seeds [p.508, col.2, ¶2—p.509, col.1, ¶.2]. They teach that AAP1 shares close homology with AAP8 and that AAP8 function is essential for sink development during reproductive phases of plants (i.e. seed development) [p.514, col.1, ¶.1; p.516, col.1, ¶.2—col.2, ¶.1]. They teach that AAP8 and proteins with related functions can enhance seed weight as well as seed number (i.e. increase seed yield via increasing yield components) [id]. They teach that having a functional AAP8 allele is necessary for proper phloem-loading of amino acids and seed development [p.509, col.1, ¶.4].
Santiago teaches the use of AAP8 (At1g10010) insertion mutants to assess function of AAP8 in Arabidopsis, and sequences relevant to detecting AAP8 (i.e. molecular markers) [p.509, col.1, ¶.4; p.518, col.1, ¶.1-5]. They teach that repression or disruption of the normal function of the WT allele of AAP8 leads to seed abortion and lowered seed yields [p.509, col.1, ¶.4]. They teach that overexpressing the functionally similar AAP1 leads to stronger reproductive sink (i.e. seed nutrient reallocation) and higher yield potentially impacting seed weight (i.e. size) as well as number [p.509, col.1, ¶.1, l.14-24; p.516, col.2, ¶.1, l.24-37].
Zhang teaches the amino acid transporter AAP8, Glyma.08G113400, (i.e. SEQ ID NO.31) is important to transport of proteins and seed formation in soybean [p.2, ¶.5;p.10, ¶.2-3; p.4, Table 1]. They teach the annotated gene sequence of soybean AAP8 (Glyma.08G113400) and relevant genomic resources for its mapping and/or manipulation [p.4, Table 1; p.11, ¶. 1 & 3]. Zhang tells the reader that genes involved in protein content of soybeans may affect yield [Abstract, last sentence].
Before the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to arrive at a method of overexpressing AAP8 to generate plants with increased yield component traits (i.e. seed number or size), as similar manipulation of the orthologous AAP1 gene is taught by Perchlik and the relationship between the two orthologs is expressly outlined by Santiago in Arabidopsis. The involvement of AAP8 in soybean seed characteristics is made obvious by the disclosure of Zhang, which also points to the relevant annotated gene and genomic resources for further manipulation(s). It would be obvious for a plant geneticist to screen for the effects of manipulating a highly homologous gene with known functional effects (i.e. AAP8) in an established way (i.e. mutating to increase expression), as the potential yield benefits of manipulating such amino acid transporter proteins in crop plants other than Arabidopsis are described by Perchlik [p.243, col.1, ¶.2; p.244, col.1, ¶.2—col.2, ¶.1] and using AAP8 sequence indicated by Zhang.
One of ordinary skill in the art would have been motivated to combine these teachings to obtain the described benefit of increased yield (i.e. increasing yield components) using known molecular targets that affect seed characteristics (i.e. the AAP1 homolog AAP8). Use of increased expression of AAP1 was known to be involved in improving NUE and seed yield, outlined by Perchlik, and it was also known that AAP8 was a close homolog to AAP1 with similar biological function, outlined by Santiago.
One skilled in the art would be motivated to apply the known method of overexpressing non-mutated AAP8 in Arabidopsis because this would increase seed yield components, as described in pea by Perchlik [p.244, col.1, ¶.2—col.2, ¶.1].
Regarding claims 17 & 24; these recite a non-Arabidopsis genetically altered plant which has at least one mutation in the functional motif and wherein the plant has increased activity of the AAP polypeptide resulting in heavier seeds (i.e. increased yield). The AAP drawn to is an ortholog of AAP8 (i.e. SEQ ID NO.31). The limitation of a non-Arabidopsis plant having overexpression of an AAP resulting in increased yield is met by Perchlik, who demonstrates this in pea [p.237, col.1, ¶.2—p.239, col.1, ¶.1; p.241, col.1, ¶.2—p.242, col.1, ¶.1; p.244, col.2, ¶.2; p.245, col.1, ¶.5]. The requirement that a modified AAP is AAP8, or a functional ortholog thereof, is met by Santiago who teaches the shared structural and functional relationships between AAP1 and AAP8 [p.514, col.1, ¶.1; p.516, col.1, ¶.2—col.2, ¶.1]. The limitation of doing this in the soybean variant of AAP8 represented by SEQ ID NO.31 is met by Zhang who describes the role of Glyma.08G113400 (i.e. soybean AAP8).
With respect to the broad limitation of ‘at least one mutation…at a position in a motif defined by SEQ ID NO.167’; Applicant defines ‘at least one mutation’ as where the AAP gene is present as more than one copy, along with numerous embodiments of mutations directed to increasing activity of the target AAP gene [Specification, p.14, l.26—p.15, l.9; p.20, l.26-28]. Broadest reasonable interpretation of this limitation, as written, is that Applicant is indicating any and all unspecified mutations, at any potential position in the motif of SEQ ID NO.167 – this encompasses any and all ways of generally overexpressing the AAP protein. Such a generic limitation requiring some non-natural modification (i.e. mutation) to increase expression is met by Perchlik’s demonstration that overexpression of AAP results in greater sink and seed yield.
Regarding claim 26; this recites the additional limitation of the genetically altered plant being a seed, which is met by Perchlik who describes the formation of seeds produced from transgenic plants, which would be assumed to be transgenic progeny absent evidence to the contrary [p.244, col.2, ¶.2; p.238, col.1, ¶.2].
Because it was clearly known at the time of filing that there was a close functional relationship between the homologs AAP1 and AAP8 and that increasing expression of AAP1 could increase sink capacity, and thus yield, in a non-Arabidopsis crop plant, claims 17, 24 & 26 are rejected as obvious in view of this prior art.
Conclusion
No claims are allowed.
Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KEITH R WILLIAMS whose telephone number is (571)272-3911. The examiner can normally be reached Mon - Fri, 9:30 - 5:30 EST.
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/KEITH R. WILLIAMS/Examiner, Art Unit 1663
/Amjad Abraham/SPE, Art Unit 1663
