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
PROSECUTION REOPENED
In view of applicant’s Appeal Brief filed on 06/13/2025, and after further considerations of the applicant’s arguments, the prosecution has been reopened. The finality of the rejection dated 02/28/2025 has been withdrawn, and a NON-FINAL action is being provided by the examiner for applicant’s due considerations and perusal.
Claims 16-20 (non-elected Group II) were previously canceled by the applicant.
Claims 1-15 and 21-25 (elected invention of Group I, treated as without traverse; “A method of making a therapeutic Mycobacteria composition…”), as presented on 01/23/2025, have been examined on their merits in this action hereinafter.
Priority
This application has been filed as US non-provisional application that gets domestic priority with effective filing date of 04/26/2023.
132 Declaration by Tsungda Hsu
The AF/D under 37 CFR 1.132 filed by inventor Tsungda Hsu on 01/23/2025 is insufficient to overcome the rejection of pending claims based upon the cited prior art at least for the reasons discussed below in the new grounds of rejection, hereinafter.
Claim Rejections - 35 USC § 103 - Withdrawn
After considering applicant’s arguments (see Appeal brief dated 06/13/2025, pages 3-8), the 103(a) rejection of claims 1-15 and 21-25 over Martin et al (2021; CN 112449604 A; PTO English translation, previously of record) taken with Hsu (2017; WO 2017/156436 A1; FOR previously of record), as previously made by the examiner, has been withdrawn.
The following contains new grounds of rejection over pending claims for applicant’s considerations as discussed below:
NOTE: 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.
Claim Rejections - 35 USC § 103 – New Grounds
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.
1. Claims 1-15 and 21-25 (as presented) are rejected under 35 U.S.C. 103 as being unpatentable over Hsu (2017; WO 2017/156436 A1; FOR previously made of record) in view of Martin et al (2021; CN 112449604 A; PTO English translation, previously made of record).
Claim 1 is directed to “A method of making a therapeutic Mycobacteria composition, comprising:
having live Mycobacteria that have a genetic trait for dimorphic colony formation;
making a single cell suspension of the Mycobacteria in a suspension fluid;
spreading the Mycobacteria suspension onto a surface of a non-liquid culture medium;
growing the Mycobacteria such that it forms colonies of both R-type and S-type morphologies on the culture medium;
identifying an S-type colony and harvesting Mycobacteria therefrom;
processing the Mycobacteria to create the therapeutic Mycobacteria composition; wherein the therapeutic composition lacks any Mycobacteria that grew from an R-type colony.”
Claim 7 (as amended) is directed to “The method of claim 1, wherein the therapeutic Mycobacteria composition is a first therapeutic Mycobacteria composition, and the method further comprises:
identifying an R-type colony and harvesting Mycobacteria therefrom;
processing the Mycobacteria harvested from the R-type colony to create a second therapeutic Mycobacteria composition;
wherein the second therapeutic composition lacks any Mycobacteria that grew from an S-type colony.”
It is noted that instant claims 1 and 7, as recited, do not specifically require any particular Mycobacterial strain or any specific “processing” step(s) per se.
See also limitations of dependent claims 2-6, 8-15 and 21-25 as currently presented.
Hsu (2017), while teaching the assays and methods for detecting an diagnosing Mycobacterial infections (see title, Abstract, and Summary of the Invention), disclose the role of phase variation in Mycobacterium tuberculosis (Mtb; see Summary of the invention on page 2, and [0033], [00125], [00127], for instance) dimorphic strains exhibiting two distinct morphotypes namely R-type (rough or raised) and S-type (smooth or spread) morphotypes (relevant to instant claims 1, 7) on non-liquid culture medium/plates; wherein the attenuated (a BSL-2 level, attenuated Mycobacteria; see page 42, [00127], for instance; relevant to instant claim 15) strain having deletion in RD1 gene (deletion of RD1 locus using homologous recombination to form mc24002 strain; see [0026], [0036], [00117], for instance; relevant to instant claims 10-12) produced both S-type and R-type colonies with distinct morphological as well as structural features (see page 34, Table 2, for instance); wherein both types of the colonies can be separated and enumerated by preparing single-cell suspensions (using suitable buffers such as PBS; see [0025], [00104]-[00105], [00107], for instance) followed by direct plating method on non-liquid media plates such as 7H10NT OADC agar plates, with or without 0.05% Tween-80 (see [0018], [00108]-[00109], [00116]-[00117], for instance; relevant to instant claims 4-6, 25); wherein the strain is an auxotroph, Mtb delta-RD1 panCD (such as having additional deletion of panCD gene; requires supplementation of D-pantothenic acid for growth on agar plate; see [0027]-[0030], for instance; relevant to instant claim 22); wherein relatively low concentration of detergent such as Tween-80 (i.e. polysorbate-80) is used for subsequent suspension because subtle morphotype variation was found to be associated with the use of this detergent in wild-type strain suggesting that it can modify colony morphology of Mtb on agar plates (see [00116], [00121], for instances; relevant to instant claim 5); wherein Hsu discloses the fact that despite the high rate of switching between the morphologies, when colonies were grown from single cells, mixed or sectored colonies were never seen (see [00118], [00122], for instance; relevant to instant claims 1, 3, 7, 8, 13, 24); wherein single-cell suspensions of the Mycobacterial strain were prepared for direct plating and spread on suitable agar plates with culture medium supplemented with D-pantothenic acid and incubated at 37 degree C for 4 weeks in order to obtain S-type and R-type colonies (see detail disclosure [00108]-[00109], for instance) that can be separated, lifted/harvested individually in separate tubes (as “an intact unit”, i.e. in order to avoid mixing), and further re-suspended in a second buffer system (such as “buffer RLT”; see [00109]; relevant to instant claim 4) for suitable microarray analysis and/or downstream genetic/structural characterizations, etc.; wherein the Mycobacteria reside in the suspension for only a short duration requiring a 20 seconds full speed vortex followed by filtration using 5 micrometer filter (see also [00107], [00111], for instance; relevant to instant claim 21); wherein incidence of phase variation was tested in both directions (i.e. S-type to R-type and visa-versa; see [00113], Fig. 3A, 3B, for instance; relevant to instant claims 9, 14) which generated about 80% S-type and about 20% R-type colonies on 7H10 OADC agar plates, whereas the wild-type strain of Mycobacterium tuberculosis produced only S-type colonies on the same medium; wherein phase conversion assays, for example, with H37Rv D-RD1 D-panCD strain (mc27000), for progeny having S- and R-morphotypes resulted in S-type yielding 104-105 CFU/colony, and R-type yielding 103-104 CFU/colony, an order of magnitude less CFU per original colony (see [00115], Fig. 5B, for instance); and wherein Hsu also discloses the variable, strain-specific effects of polysorbate-80 (Tween-80, an emulsifying agent) on the morphotypes of wild-type strain H37Rv (see [00116], for instance), pointing to subtle but distinct morphotype variations over a period of time on 7H10 OADC agar plates supplemented with Tween-80 at 0.05% concentration (see also disclosure in [00117], for instance), whereas “tyloxapol which is also an emulsifying agent did not alter colony morphotypes of H37Rv DRD1” strain (see [00121], for instance), suggesting variable, strain-specific effects of different detergents on growth and morphotypes of various Mycobacterial strains.
More importantly, Hsu discloses the enrichment of phase-specific immunogens using S-type colony (“S-type immunogens”), or R-type phase variant (“R-type immunogens”) for developing monoclonal antibodies (see [00128], for instance) as an example of downstream applications for the two different immunogenic colony morphotypes. In addition, Hsu discloses the advantageous pleomorphic phenotypes or phase variations in Mtb that “differ in sensitivity”, and help it as an effective pathogen in host’s lungs and macrophages (that are primary pathogen clearing cells), wherein “R-type colonies pointed to their readiness for intracellular (hypoxic) growth”, and “S-type colonies grew as fast compared to R-type colonies on aerated 7H10 agar plates”, and “R-type colonies seem to be more hydrophobic”, wherein the disease cycle of M. tuberculosis “includes both the growth of M. tuberculosis within an individual and its contagion from person to another” (see entire [0033], for instance); wherein Hsu discloses the fact “…that S-type colonies, which it is hypothesized grow favorably in the lung cavity, grew 2-3 times faster in aerobic conditions than R-type colonies on 7Hl0 agar plates, consistent with the observations made by others (Yuan 1998). Therefore, it is hypothesized that S- and R-type phase variants are adapted to aerobic and hypoxic niches, respectively, and may also function in a complementary fashion in manipulating the host immune response” (see [00125], for instance), and therefore directly pointing to different sensitivity of the two morphotypes adapted to different growth conditions and niches (see also [00127], page 42 1st paragraph, wherein Hsu states that “…S-type and R-type are adapted to aerobic (in lung cavities) and hypoxic (inside macrophages in granulomas) niches, respectively”), and thus encompassing different functional and/or immunogenic profiles thereof (see also structural differences shown in Table 2 starting on page 34, for instance), which are useful for detection, diagnosis (see claims 1-7, 18-24, starting on page 57, for instance), as well as in preparation of distinct antigenic preparations that can be used for immunization of subjects in need (see also [00127] on page 42, 1st paragraph, that states “…it is advantageous for some S-type Mtb to convert to R-type phase variants before infecting new patients where R-type will be phagocytosed by macrophages into hypoxic phagosomes. It is therefore logical to postulate that S- and R-type phase variants may function in a complementary fashion in manipulating the immune response as S-type phase variants are likely to be destroyed and the associated antigens are presented to the host immune system”), and thus provides direct motivation for an artisan in the art to separate the two different morphotypes of Mycobacterial strains in order to prepare effective therapeutic compositions for them, as per need.
However, the step of “processing the Mycobacteria to create the therapeutic Mycobacteria composition” (instant claims 1, 7), wherein the harvested Mycobacteria comprises lyophilizing the Mycobacteria” (instant claim 2), has not been explicitly disclosed and/or demonstrated by the cited prior art reference of Hsu, as discussed above.
Martin et al (2021; citations as per English translation of record) disclose method of making freeze-dried vaccine composition comprising isolated, live, attenuated Mycobacteria (Mycobacterium tuberculosis complex; see Abstract on page 2, and claims on pages 21-23) belonging to M. tuberculosis MTBVAC strain, wherein the cultured Mycobacterial preparation (comprising at least 3 x 103 CFU per 0.1 ml of separated strains in water or more; see claims 9-13) is added with stabilizers or excipient and lyophilized into a freeze-dried composition; wherein the composition is useful in prevention or treatment of patients having tuberculosis or at risk patients in need thereof (i.e. therapeutic compositions). Although, Martin et al employ a different strain of Mycobacterium, the step of preparing vaccine composition by freeze-drying or lyophilizing attenuated Mycobacteria as antigen composition, has been nevertheless fully disclosed.
Thus, given the detailed disclosure from Hsu for all the required method steps of making single-cell suspension of a dimorphic strain of Mycobacteria (see Hsu teachings above), direct plating and spreading on to a non-liquid culture medium (i.e. semi-solid agar plates), growing said mycobacteria to form both types of colony morphotypes including S-type and R-type colonies, detecting, identifying and harvesting/collecting separately each type of colonies for further characterization, and given the disclosure from Martin et al (see teachings discussed above) for making lyophilized vaccine compositions comprising live, attenuated, Mycobacterial strains using addition of suitable stabilizers for effective freeze-drying method (see teachings from Martin et al, above), it would have been obvious to an artisan of ordinary skill in the art to modify the method disclosed by Hsu such that it incorporates the step of processing the harvested Mycobacterial morphotypes (S-type and R-type colonies separately, if so desired) using the same freeze-drying technique (with or without addition of suitable stabilizers and/or excipients, etc.) as already successfully taught and/or demonstrated (by Martin et al) for preparing a vaccine composition suitable for clinical use in subjects in need thereof. Since, Hsu already teaches in all the details as to how to make single-cell suspensions, spread and/or plate, grow and/or separately collect both types of morphotypes of a suitable attenuated, auxotrophic, dimorphic Mycobacterial strain (for instance, H37Rv DRD1; see detailed teachings above) using a non-liquid, semi-solid agar culture medium, and in addition provides the motivation for using separated R-type and S-type immunogens for various downstream applications (such as for making antibodies, or for raising and/or manipulating the host immune response in subjects in need; see Hsu teachings above, [00125], [00128], for instance), it would have been obvious to an artisan of ordinary skill in the art to prepare and successfully process both types of morphotypes of the dimorphic Mycobacterial strain separately, if desired, especially given the fact that Hsu discloses that the colony morphotypes do not produce mixed or sectored progeny and remain true to their morphology once separated (i.e. do not revert; see Hsu, [00115]-[00118], for instance), specifically when using the RD1 locus gene deletion strain of Mtb H37Rv. Therefore, unless evidence provided on record (which is currently lacking; see figures 1-2) to the contrary, such modification in the method of making therapeutic Mycobacteria compositions by incorporating a processing step that involves lyophilizing (i.e. freeze-drying) the Mycobacterial composition that comprise separated S-type and R-type morphotypes of Mycobacterial strain (see instant claims 1 and 7, in particular), as taught by the combined teachings and/or suggestions from Hsu taken with Martin et al, would have been obvious and/or fully contemplated by an artisan of ordinary skill in the art.
The specific limitations of instant claim 4 that requires two different “suspension fluids” would have been obvious to an artisan in the art as Hsu already discloses such buffers including phosphate buffered saline (PBS) and “buffer RLT” that can be used for suspending initial parent culture and later for separated morphotypes (see detailed teachings of Hsu above; [00109], for instance). In addition, Martin et al also disclose the fact that one can add stabilizers (such as sucrose and sodium glutamate) in the culture medium before the freeze-drying step (see Martin et al, translation on page 11, for instance; see also page 14, 1st paragraph) in order to prepare stable, lyophilized therapeutic compositions, as per need.
In addition, the limitations of instant claim 5 for using “non-liquid culture medium” that “lacks polysorbate-80 or has a low content thereof” (regarding “low content”; see instant disclosure, page 8, last paragraph, in particular) would have also been obvious to an artisan of ordinary skill in the art because Hsu explicitly discloses the variable, strain-dependent effects of emulsifiers/detergents including polysorbate-80 (i.e. Tween-80) and another emulsifier (such as “tyloxapol”; see Hsu teachings above; [00121], for instance), and therefore use of a lower amount or a lower concentrations of Tween-80, for example (or suspension buffers with or without an emulsifier depending on the type of strain being used in the process), would have been taken as a result-effective variable that could be successfully modified and/or optimized by an artisan of ordinary skill in the art, as per need. It is to be noted that instant claims (see claims 1 and 7, in particular) are not limited to any particular dimorphic Mycobacterial strain or any specific type or amount of an emulsifier per se.
Also, the limitations of instant claim 23, “wherein at least 50% of the Mycobacteria in the single cell suspension are dissociated into individual single cells”, would have been obvious to an artisan of ordinary skill in the art given the detailed teachings from Hsu (see detailed teachings discussed above; [00107]-[00108], for instance) for preparing such single-cell suspensions of Mycobacteria that were vortexed and gravity filtered (through 5 microns filter), and later used for direct plating on the “non-liquid culture medium” (i.e. 7H10 OADC agar plates), from where separate R- and S-type colonies are identified, counted, and separately harvested. Therefore, an artisan in the art would have successfully prepared and/or optimized the percentage of individual cells, for instance, based on the counting of single colonies resulting on the culture plates, as per need. Therefore, the process as currently claimed fails to distinguish itself over the combined teachings and/or suggestions from the cited prior art references of Hsu when taken with the disclosure from Martin et al for preparing a therapeutic Mycobacteria composition, as discussed above.
Thus, the claim as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the invention, as currently claimed.
As per MPEP 2111.01, during examination, the claims must be interpreted as broadly as their terms reasonably allow. In re American Academy of Science Tech Center, F.3d, 2004 WL 1067528 (Fed. Cir. May 13, 2004)(The USPTO uses a different standard for construing claims than that used by district courts; during examination the USPTO must give claims their broadest reasonable interpretation.). This means that the words of the claim must be given their plain meaning unless applicant has provided a clear definition in the specification. In re Zletz, 893 F.2d 319, 321, 13 USPQ2d 1320, 1322 (Fed. Cir. 1989).
Examiner’s Response to Arguments
Applicant’s arguments with respect to claim(s) of record filed with Appeal Brief dated 06/13/2025 (see Appeal Brief, pages 3-8 regarding withdrawn 103 rejection) have been considered but are moot because of new ground of rejection made in this office action, as discussed in details above.
Conclusion
NO claims are currently allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SATYENDRA K. SINGH whose telephone number is (571)272-8790. The examiner can normally be reached M-F 8:00- 5:00.
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SATYENDRA K. SINGH
Primary Examiner
Art Unit 1657
/SATYENDRA K SINGH/
Primary Examiner, Art Unit 1657