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 .
Declaration/Affidavit
The affidavit under 37 CFR 1.132 filed 3/31/2026 is insufficient to overcome the rejection of claims 1-3 and 7-18 based upon 35 USC § 112(a) for lack of written description. A declaration would overcome the rejection with a showing of evidence that a broader genus of morphogenetic regulators was known by the inventors and evidence showing that a mutation in one morphogenetic regulator (that is shown in application as mut MreB) can indeed be extrapolated to other morphogenetic regulators. However, the declaration in i) #4-5, pg. 1 of dec, directs one to the specification where genera of morphogenetic regulators are described and one is modified, then continues to provide examples “include cytoskeletal proteins such as MreB, proteins that control cytoskeletal function such as SulA and Min proteins, and peptidoglycan synthases such as PBP2”; ii) #6-8, pg. 2 of dec states, “specification further discloses modifying such morphogenetic regulators, including by substitution, deletion, insertion, addition, mutation, or altered expression, in order to influence cell growth behavior.” And continues to provide the example of a) mutating the cytoskeletal protein MreB and b) inducing expression of SulA. Both examples show reduction of E.coli cell growth; iii) #9-11, pg. 2 of dec states that these examples are “specific categories of morphogenetic regulators in E coli”.
However, the latter is a conclusory statement instead of evidentiary data showing such possession of specific categories of morphogenetic regulators in E coli. Such conclusory statements do not reconcile the inadequacies of the limited disclosure of the broad genus of morphogenetic regulators to what is known in the art and do not address the rejection previously made. The opinion-based declaration extending the good results shown in the specification to non-exemplified species is not indicative of the broad genus in question.
Response to Arguments
Applicant's arguments filed 3/31/2026 have been fully considered but they are not fully persuasive. Arguments pertaining to any remaining rejections are addressed in this Office Action.
Status of the Claims
This action is in response to papers filed 3/31/2026 and in which specification was amended, claim 1 was amended, claim 4 was canceled, and no new claims were added. All amendments are entered.
Claims 1-3 and 5-20 are under consideration.
Amendments
All of the amendments have been thoroughly reviewed and entered.
Applicant has:
amended claim 1 and cancelled claim 4 to overcome the 35 USC § 112(a) rejection; the 112(a) rejection of claims 1-3 and 7-18 is not withdrawn. A new rejection necessitated by amendment is presented in this office action.
argued, see Pg. 7-8, filed 3/31/2026, with respect to the 35 USC § 112(a) rejections; arguments have been fully considered but are not fully persuasive for the reasons discussed in this office action.
Any rejection or objection not reiterated herein has been overcome by amendment. Any rejections and objections not reiterated in this action have been withdrawn. In addition, this office action contains new objections and rejections regarding newly added claims.
Priority
A certified English language translation of priority document JP2019-142388 has been properly added to the priority chain. A statement that the translation of the certified copy is accurate has also been received. The certified copy provides support for the priority date to be the filing date of the foreign application; i.e., August 1, 2019.
Claim Rejections - 35 USC § 112
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-3 and 7-18 remain 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 claim(s) contains 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
A new matter rejection maintained for previously presented claim.
The written description rejection was made in the Office action mailed 10/01/2025 has been rewritten to address the limitation not overcome by amendment.
I. Maintained New Matter Rejection
MPEP 2163.II.A.3.(b) states, “when filing an amendment an applicant should show support in the original disclosure for new or amended claims” and “[i]f the originally filed disclosure does not provide support for each claim limitation, or if an element which applicant describes as essential or critical is not claimed, a new or amended claim must be rejected under 35 U.S.C. 112a, as lacking adequate written description". According to MPEP § 2163.I.B, "While there is no in haec verba requirement, newly added claim limitations must be supported in the specification through express, implicit, or inherent disclosure" and "The fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, applicant was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc., 935 F.2d at 1563-64, 19 USPQ2d at 1117".
Regarding claim 16, the limitation of “and combinations thereof” with respect to morphogenetic regulators appears to represent new matter. No specific basis for this limitation was identified in the specification, nor did a review of the specification by the examiner find any basis for the limitation. Since no basis has been identified, claim 16 is rejected as incorporating new matter.
Response to Arguments
Applicant's arguments filed 3/31/2026 have been fully considered and they are persuasive for claim 1 as the amendment has overcome the rejection for claim 1. The new matter rejection of claim 1 has been withdrawn.
However, claim 16 recites similar language and was not amended. Therefore the new matter rejection is maintained for the same limitation in claim 16.
Applicants may amend claim 16 in the same manner as previous claim 1 was amended to overcome this rejection.
Written Description Rejection
MPEP 2163.II.A.3.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention”.
The purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
For claims drawn to a genus, MPEP § 2163 states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
II. Rewritten Rejection
This is a new rejection necessitated by amendment.
Claim 1 recites, “... E.coli…wherein the cell growth of the recombinant cells is reduced in the growth reduction step by using recombinant cells, and the recombinant cells comprise at least one morphogenetic regulator selected from: a cytoskeletal protein, a protein that controls a function of a cytoskeletal protein, and a peptidoglycan synthase … wherein the morphogenetic regulator is a modified morphogenetic regulator that has been modified by…. to reduce the cell growth of the recombinant cells”.
Claim 16 recites similar language except that it is not limiting the modification to to reduce the cell growth of the recombinant cells.
Scope of the Invention
In the instant case, the genera are
at least one morphogenetic regulator selected from: a cytoskeletal protein, a protein that controls a function of a cytoskeletal protein, and a peptidoglycan synthase; wherein each of: a cytoskeletal protein and a protein that controls a function of a cytoskeletal protein, are a subgenus on their own.
above modified morphogenetic regulator (by modifications from the recited list of: substitution, deletion, insertion, addition, or mutation) to reduce the cell growth of the recombinant cells.
The broadest reasonable interpretation of the scope of these genera are E.coli carrying a heterologous gene for a protein, and the E.coli is a recombinant cell further comprising a morphogenetic regulator selected from: a cytoskeletal protein, a protein that controls a function of a cytoskeletal protein, and a peptidoglycan synthase has been modified (claims 1 and 16), in order to differentiate the morphogenetic regulator from its wild-type equivalent.
Disclosure of a Complete or Partial structure
Regarding the morphogenetic regulator, “Morphogenetic regulator” is described in [0011] of the disclosure to mean a protein related to cell morphogenesis or control of cell morphology. Specific examples of the morphogenetic regulator can include a cytoskeletal protein, a protein that controls a function of a cytoskeletal protein, a peptidoglycan synthase, and the like. Thus, the genus of morphogenetic regulators, described by Applicants, and as recited, is large.
However, in the specification, i) within the subgenus of cytoskeletal protein only the wild-type (WT) MreB is identified in the disclosure by SEQ ID NO: 1 [0022] as a morphogenetic regulator, which is then modified, and ii) within the genus of proteins which control the function of the cytoskeletal protein (morphogenetic regulator), examples in prokaryotes can include sulA (SEQ ID NO: 7) [0024], which is not modified in instant disclosure.
Regarding the modified morphogenetic regulator, the disclosure describes “Modified morphogenetic regulator” [0015] to mean various kinds of modifications such as modified by a substitution, deletion, insertion, addition, or mutation or artificial expression regulation, and then describes "mutant morphogenetic regulator" [0016] to mean a morphogenetic protein with any kind of mutation comprising a substitution, deletion, insertion, and/or addition of one or more amino acid residues as compared to the amino acid sequence of a wild-type morphogenetic regulator. Thus, the genus of modifications and mutations to the large genus of morphogenetic regulators is large as well. Various single amino acid substitutions in MreB are then listed. The mutations and transformations are made by known methods.
Regarding to reduce the cell growth of the recombinant cells, functionally, the mutant morphogenetic regulator must continue to allow for the growth of the recombinant cells but a slower rate than unmodified cells (Fig. 2 – 3 and 7). The inventive concept requires the mutant morphogenetic regulator keeps the cells arrested in a growth reduction step [BRI]. Further such a mutant protein coexists with the endogenous unmodified protein.
This functional amendment reduces the genus of modified morphogenetic regulators to modifications that will to reduce the cell growth of the recombinant cells. However, claim 16 does not have this amendment.
Species Not Described
As discussed in “Disclosure of a Complete or Partial structure” section above, ii) Examples of proteins which control the function of the cytoskeletal protein (morphogenetic regulator), in prokaryotes can include sulA (SEQ ID NO: 7) [0024], and this is described. However nothing in sulA is shown to be modified rather its expression is induced. Therefore, induction of sulA cannot be considered to be within the scope of wherein the morphogenetic regulator is a modified morphogenetic regulator despite the showing of induction of sulA resulting in reduce the cell growth of the recombinant cells.
For claim 16, the genus of morphogenetic regulator selected from: a cytoskeletal protein, a protein that controls a function of a cytoskeletal protein, and a peptidoglycan synthase; wherein each of: a cytoskeletal protein and a protein that controls a function of a cytoskeletal protein, are not limited in any way. Therefore, the subgenera encompassed are large on their own and only mutation within MreB is described.
State of the Art
The written description requirement may be met by providing a representative number of species of the genus and/or in light of the state of the art. With regard to the state of the art, Jones (Jones et al., Cell, Volume 104, Issue 6, 2001, Pages 913-922, ISSN 0092-8674) teaches that the cell wall and various filamentous actin-like structures are responsible for bacterial cell morphology (Jones Summary, Introduction).
With respect to cell-wall, Cho (Cho H. et al., Nat Microbiol 1, 16172, 2016) teaches that multi-protein complexes organized by cytoskeletal proteins are essential for cell wall biogenesis in most bacteria (Cho, 1st sentence of abstract). Rod-shaped bacteria typically use two essential cell wall biogenesis machines: cell elongation to include the proteins: RodA, a SEDS-family protein, and PBP2, a class B penicillin-binding protein (bPBP) with transpeptidase (TP) activity that forms cell wall crosslinks, organized by dynamic filaments of the actin homolog MreB; and cell division to include a different multi-protein machine, the divisome, organized by the tubulin homolog FtsZ (Cho, pg. 2, 2nd paragraph). Higher-level control of these proteins also exist, for. e.g., Cho describe blocking both FtsZ and MreB activity by expressing SulA (Cho, pg. 4, 2nd paragraph).
With respect to the filamentous actin-like structures, Jones teaches the significance of MreB in determining cell morphology (Jones title, abstract, and last paragraph of introduction). Jones teaches that even single amino acid substitutions in MreB can effectuate morphological change (Jones Figure 4. Effects of Missense Mutations in mreB on Cell Shape). Further, Jones teaches that the mreB gene is essential in some bacteria but not in E. coli (Jones bridging pg. 913 and 914); i.e., mreB mutation will not be lethal to E.coli.
Jeong (KR20040026508A), as evidenced by its machine translation, also teach a method for increasing production of exogenous protein in E. coli. Jeong’s method encompasses co-expressing the ftsA and ftsZ genes with the exogenous protein. As evidenced by instant disclosure Jeong experimentally show that co-expressing either FtsA or FtsZ singly did not result in increased exogenous protein production (pg. 5, 3rd para). However, a combination of ftsA and ftsZ proved to be beneficial in increased exogenous protein production in E. coli. See recitation from pg. 10:
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Jeong ascribe the increased productivity of the foreign protein to the inhibition of bacterial filamentation and improving cell growth (pg. 3, 3rd para). Jeong observe differences in cell morphology following transformations; each of FtsA and FtsZ alone resulted in abnormal morphology but the combined transformation did not. (Figs. 9 – 10).
Thus, it is noted that the prior art teaches that several proteins (morphogenetic regulators), interacting with each other or regulated at a higher level, are at play in determining a cell’s morphology. The prior art also teaches that functional outcomes of morphogenetic regulators differ when used singly or in combination.
Changes appearing in current rejection as a result of the amendment: to reduce the cell growth of the recombinant cells, that differ from the rejection presented in the Non-Final:
Claim 1 as instantly amended still invokes 112a because description of induced expression of SulA - a protein that controls cytoskeletal function does not support the subgenus of modified protein that controls a function of a cytoskeletal protein, despite the limitation to reduce the cell growth of the recombinant cells.
Accordingly, with respect to instant claims, the breadth of the phrase “a protein that controls a function of a cytoskeletal protein… that has been modified by a substitution, deletion, insertion, addition, or mutation” embraces a large genus of regulators as modifications from the recited list of: substitution, deletion, insertion, addition, or mutation, or combination of any of these within morphogenetic regulators will result in unfathomable amount of modifications unless limited to the function of to reduce the cell growth of the recombinant cells.
Claim 16 is not further limiting the broad genus within the scope of the claim.
Dependent Claims
Claims 2-3, 7 – 15, and 17 - 18 do not further limit the genus of nucleic acid molecules so as to resolve the issues above, and are therefore, not sufficiently described for at least the reasons above.
Conclusion of Written Description
Therefore, the examiner concludes there is insufficient written description support for
i) the instantly claimed subgenus of a protein that controls a function of a cytoskeletal protein… that has been modified by a substitution, deletion, insertion, addition, or mutation;
and ii) For claim 16 and its dependent claims only: the instantly claimed genus of morphogenetic regulator selected from: a cytoskeletal protein, a protein that controls a function of a cytoskeletal protein, and a peptidoglycan synthase; wherein the morphogenetic regulator has been modified by a substitution, deletion, insertion, addition, or mutation.
The specification solely describes one modified morphogenetic regulator - mutant MreB. One species (MreB) example is not representative of the complete structure of the such a diverse genus as “modified morphogenetic regulator”. The examiner concludes that there is insufficient written description of the instantly claimed genera. Only methods comprising inducing sulA and modifying a cytoskeletal protein, which includes Ala53Thr in MreB, within E.coli cells, and not the full breadth of the claims, is supported by Applicant’s disclosure.
Dependent claims 2-3, 7-15, and 17-18 are rejected for not remedying the deficiencies in the claims they depend from.
Examiner Suggestion: Amend the claims to recite or inducing sulA. In addition, amend claim 16 to limit the broad genera of morphogenetic regulators to a genera that is supported by the disclosure and/or prior art.
Response to Arguments
Applicant’s arguments, see Pgs. 7-8, filed 3/31/2026, with respect to rejections to previous claims 1 - 18 have been considered. With respect to the arguments in response to the 112(a) written description rejection, Applicant’s arguments have been fully considered but are not fully persuasive. The previous rejection under 35 USC § 112(a) with respect to written description has been: i) rewritten to address only one subgenus that has not been overcome by amendment, and ii) maintained to reiterate the rejection for claim 16. The rejection presented above also includes maintaining 112a New Matter of claim 16.
Applicants essentially assert that: 1) the claims have been amended to remove the limitation “and combinations thereof” and 2) elaborate on the writings presented in the declaration; i.e.,
i) the specification discloses two species: a structural mutation (A53T) introduced directly into the cytoskeletal protein MreB and expression of SulA - a protein that controls cytoskeletal function. Both examples slow cell growth. Since these two examples are not variations of the same approach, rather represent two fundamentally different strategies for achieving the claimed result - one by directly mutating a cytoskeletal protein, and one by modulating the expression of a division control protein, they provide support for a broader genus than either example alone would suggest.
ii) the genus presented in the claims is a defined and limited functional class of proteins well known in the art - well-characterized functional categories of proteins in E. coli: cytoskeletal proteins such as MreB, proteins that control cytoskeletal function such as SulA and Min proteins, and peptidoglycan synthases such as PBP2. Examiner's own cited prior art supports this point.
Regarding 1) this limited amendment has overcome a part of the 112a rejection; in addition, regarding claim 1, claim 1 has been amended to recite the limitation " to reduce the cell growth of the recombinant cells”. The latter amendment narrows down the list of subgenera of modified morphogenetic regulator selected from: a cytoskeletal protein, a protein that controls a function of a cytoskeletal protein, and a peptidoglycan synthase. Therefore, the genera within this scope no longer invoke 112a written description.
regarding 2), the declaration does not clarify issues raised in the 112a rejection. Deficiencies in the declaration were discussed at the onset of this office action. Specifically, while a MreB mutation is discussed in the specification, the declaration only provides specification paragraph citations of other morphogenetic regulators and mutations therein. These statements are not persuasive because: the scope of the claims still refers to a broad genera. The examples provided are well-described in the disclosure and the prior art. However, they are just that – examples. Without structure/function correlation provided in the disclosure or declaration to allow a skilled artisan to extrapolate from the provided example to other species in the genera (well-known or not, discovered or yet undiscovered), there is no written description support.
For e.g., Jeong’s (KR20040026508A) disclosure in the prior art section and which is further elaborated: It was recognized in the prior art, as evidenced by Jeong, that an unmodified, unmutated form of FtsZ increases the production of exogenous proteins in a recombinant bacterium. For e.g., Jeong discloses increased transgene expression when FtsA and FtsZ are both coexpressed with the transgene (whole disclosure). In contrast, instant disclosure states FtsZ is a morphogenetic regulator [0013]. Further, given the BRI of instant claims, FtsZ is required to be modified as per instant invention in order to allow for increased transgene expression; i.e., the claims as broadly written do not exclude a modified “FtsZ” from the genus of “modified morphogenetic regulator”.
Therefore, the rejection is maintained for reasons of record set forth in the non-final office action of 10/24/2024, 5/7/2025, and 10/01/2025.
Applicants arguments are not dispositive. The §112a rejection is maintained.
Allowable Subject Matter
Regarding claims 5-6 and 19-20, an Alanine to Threonine mutation on amino acid number 53; i.e. A53T point mutation, in MreB is not taught in the prior art.
The closest prior art is: Shiomi (Shiomi, D., et al., (2013), Molecular Microbiology, 87: 1029-1044). Shiomi study mutations in cell elongation genes mreB, mrdA and mrdB that suppress the shape defect of RodZ-deficient bacterial cells. Several suppressor mutants (bearing single amino acid substitution mutations in mreB) of rodZ mutant cells whose growth was faster and had a restored cell shape in rich medium were isolated. Some of the mutants are neutral amino acid substitutions such as A to T substitutions.
The following regarding MreB are taught by Shiomi:
i) MreB is one of several genes essential for maintenance of proper cell shape in bacteria.
ii) Single amino acid substitution mutations of MreB result in pleiomorphic/pleiotropic phenotypes because of interactions of MreB with other cytoskeletal determining proteins.
And
iii) A change of cell shape affects the integrity of the cell wall, cell membrane and cellular metabolism; the cell shape and cell size are significant factors for adaptive proliferation of bacteria in their particular environments.
The following regarding MreB are not taught by Shiomi:
i) A53T point mutation in MreB is one of the single amino acid substitution mutations isolated / identified as a suppressor mutant.
ii) A53T point mutation in MreB (if present) affects cell shape.
Thus, A53T point mutation in MreB, as cited in instant claims 5 and 6 is an unexpected and surprising mutant morphogenetic regulator.
Therefore, the subject matter of the specific MreB mutant in claims 5-6 and 19-20 is free of the prior art.
Claims 5-6 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
Claims 1-3 and 7–18 are rejected.
Claims 5-6 are objected to.
Claims 19 - 20 are allowable.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SHABANA MEYERING, Ph.D. whose telephone number is (703)756-4603. The examiner can normally be reached M - F: 9am to 5pm EST.
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SHABANA S. MEYERING, Ph.D.
Examiner
Art Unit 1635
/SHABANA S MEYERING/Examiner, Art Unit 1635
/CATHERINE KONOPKA/Primary Examiner, Art Unit 1635
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