DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Applicants’ claim amendment and response of 10/16/2025 are acknowledged. Claims 1-3, 6, 17-18, 21-29, 31 and 33-34 have been amended. Claim 4-5, 15 and 32 have been canceled.
Status of Claims
3. Claims 1-3, 6, 17-18, 21-29, 31 and 33-34 are pending. Claims 1-3, 6, 17-18, 21-29, 31 and 33-34 have been amended. Claim 4-5, 15 and 32 have been canceled.
Claims 7-14, 16,19, 20 and 30 have been canceled previously.
Sequence Compliance
4. Sequence identifiers for nucleotide and/or amino acid sequences in pages 59, 67, 68, 71 and table 8 have been entered. The sequences are in compliance now.
Claim Objection Withdrawn
5. Objection to claim for the abbreviation of numerous proteins, is withdrawn for cancelation of said abbreviations.
Claim Rejections - 35 USC § 112 Moot
6. Rejection of claim 5 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement (This is a biological deposit rejection), is moot in view of cancelation of said claim.
Claim Rejections - 35 USC § 112 Moot
7. Rejection of claims 4-5, 15 and 32 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, is moot in view of cancelation of said claims.
Double Patenting Moot
8. Rejection of claim 5 on the ground of non-statutory double patenting as being unpatentable over claim 1 of co-pending Application No. 18/693, 284, is moot in view of cancelation of said claim.
Claim Rejections - 35 USC § 103 Moot
9. Rejection of claims 4-5, 15 and 32 under 35 U.S.C under 35 U.S.C. 103 as being unpatentable over Grosshennig et al. (Infection and Immunity vol.81, no.3, pp.896-904, 2013) in view of Baseman et al. (US20090104185 A1) and Waites et al. (Clinical Microbiology Reviews, vol. 30, no. 3, pp. 747-809, 2017), is moot in view of cancelation of said claims.
10. Rejection of claims 4-5 under 35 U.S.C. 103 as being unpatentable over Grosshennig et al. (Infection and Immunity vol.81, no.3, pp.896-904, 2013) in view of Baseman et al. (US20090104185 A1) and Waites et al. (Clinical Microbiology Reviews, vol. 30, no. 3, pp. 747-809, 2017) and further in view of Hames et al. (Journal of Bacteriology vol. 191, no.3, pp. 747-753, 2008) and Eduardo et al. (Journal of Biological Chemistry vol. 286, no.41 pp, 35367-35379, 2011), is moot in view of cancelation of said claims.
Claim Rejections - 35 USC § 112 Withdrawn
11. Rejection of claims 1-3, 6, 17-18, 21-24, 31 and 33-34 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, is withdrawn in view of applicants’ amendments and response of 10/16/2025.
Double Patenting Maintained
12. Rejection of claims 1, 2, 3, 17, 18 on the ground of non-statutory double patenting as being unpatentable over claim 1 of co-pending Application No. 18/693, 284, is maintained.
The rejection was as stated below:
Although the claims at issue are not identical, they are not patentably distinct from each other because claims 1 and 2 of instant application recite:
Amended Claim 1. A genetically modified Mycoplasma pneumoniae bacterium comprising a deletion, substitution, and/or insertion of one or more nucleotides in the operon of the Ca2+ dependent cytotoxic nuclease gene (MPN133) and the operon of the ADP-ribosyltransferase CARDS gene (MPN372) resulting in their removal or inactivation; wherein the genetically modified Mycoplasma pneumoniae bacterium propagates in the lungs of a host organism; wherein the pathogenicity and/or immunogenicity of the genetically modified Mycoplasma pneumoniae bacterium is reduced as compared to a M129-B7 Mycoplasma pneumoniae bacterium; and wherein the reduction in pathogenicity and/or immunogenicity is characterized by a reduction of toxicity by at least 30% upon introduction into the host organism as compared to the M129-B7 Mycoplasma рпеumоniae bacterium introduced into an otherwise identical host organism.
Claim 2. The genetically modified Mycoplasma pneumoniae bacterium of claim 1, wherein the bacterium further comprises a deletion, substitution, and/or insertion of one or more nucleotides in a gene or operon encoding a peroxide producing protein.
On the other hand, claim 1 of 18/693,284 recites:
Claim 1. A genetically modified Mycoplasma bacterium comprising:
in its genome a deletion, substitution, and/or insertion of one or more nucleotides in the operons of the Ca2+ dependent cytotoxic nuclease gene (MPN133) or orthologues thereof and ADP-ribosyltransferase CARDS gene (MPN372) or orthologues thereof, that reduce the pathogenicity and/or immunogenicity of the genetically modified Mycoplasma bacterium as compared to a reference M129-B7 Mycoplasma pneumoniae bacterium, the reduction in pathogenicity and/or immunogenicity being characterized by a reduction of toxicity by at least 30% upon introduction into a host organism when compared to the reference M129-B7 Mycoplasma pneumoniae bacterium,
wherein the genetically modified Mycoplasma bacterium further comprises in its genome an oligonucleotide arrangement, said oligonucleotide arrangement comprising:
a first nucleotide sequence encoding a first heterologous exopolysaccharide hydrolyzing enzyme under the control of a promoter or a functional variant of the promoter or fragment thereof which is active in the genetically modified Mycoplasma bacterium, and wherein the exopolysaccharide hydrolyzing enzyme is Dispersin B, and
ii) at least one further nucleotide sequence encoding further heterologous exopolysaccharide hydrolyzing enzymes under the control of a promoter or a functional variant of the promoter or fragment thereof which is active in the genetically modified Mycoplasma bacterium, and wherein the further exopolysaccharide hydrolyzing enzymes are selected from the group consisting of: Alginate lyase AI-II', PelAh, PslGh, or any combination thereof.
The claims of both applications are drawn to the same subject matter and are not patentably distinct. Because both applications are drawn to genetically modified Mycoplasma bacterium, wherein the Mycoplasma bacterium comprises in its genome a deletion, substitution, and/or insertion of one or more nucleotides in the operon of the Ca2+ dependent cytotoxic nuclease gene (MPN133) and the operon of the ADP-ribosyltransferase CARDS gene (MPN372) that reduce the pathogenicity and/or immunogenicity of the Mycoplasma bacterium as compared to a reference Mycoplasma M129-B7 bacterium. Depended claims 2, 3, 17, 18 are not also distinct.
This is a provisional non-statutory double patenting rejection because the patentably indistinct claims have not in fact been patented. Therefore, the rejection is maintained.
In response to applicants’ arguments that limitations of claim 15 now canceled in included in claim 1, the limitations recites wherein the reduction in pathogenicity and/or immunogenicity is characterized by a reduction of toxicity by at least 30% upon introduction into the host organism as compared to the M129-B7 Mycoplasma рпеumоniae bacterium introduced into an otherwise identical host organism.
claim 1 of 18/693,284 recites
A genetically modified Mycoplasma bacterium comprising: in its genome a deletion, substitution, and/or insertion of one or more nucleotides in the operons of the Ca2+ dependent cytotoxic nuclease gene (MPN133) or orthologues thereof and ADP-ribosyltransferase CARDS gene (MPN372) or orthologues thereof, that reduce the pathogenicity and/or immunogenicity of the genetically modified Mycoplasma bacterium as compared to a reference M129-B7 Mycoplasma pneumoniae bacterium, the reduction in pathogenicity and/or immunogenicity being characterized by a reduction of toxicity by at least 30% upon introduction into a host organism when compared to the reference M129-B7 Mycoplasma pneumoniae bacterium.
Therefore, the rejection is maintained.
Claim Rejections - 35 USC § 103 Maintained
13. Rejection of claims 1-3, 6, 17-18, 21-24 and 31 under 35 U.S.C. 103 as being unpatentable over Grosshennig et al. (Infection and Immunity vol.81, no.3, pp.896-904, 2013) in view of Baseman et al. (US20090104185 A1) and Waites et al. (Clinical Microbiology Reviews, vol. 30, no. 3, pp. 747-809, 2017), is maintained.
The rejection was as stated below:
Claims 1-6, 15, 17-18, 21-24 and 31-32 are rejected under 35 U.S.C. 103 as being unpatentable over Grosshennig et al. (Infection and Immunity vol.81, no.3, pp.896-904, 2013) in view of Baseman et al. (US20090104185 A1) and Waites et al. (Clinical Microbiology Reviews, vol. 30, no. 3, pp. 747-809, 2017). All art of record applicants’ search report.
Amended Claim 1. A genetically modified Mycoplasma pneumoniae bacterium comprising a deletion, substitution, and/or insertion of one or more nucleotides in the operon of the Ca2+ dependent cytotoxic nuclease gene (MPN133) and the operon of the ADP-ribosyltransferase CARDS gene (MPN372) resulting in their removal or inactivation; wherein the genetically modified Mycoplasma pneumoniae bacterium propagates in the lungs of a host organism; wherein the pathogenicity and/or immunogenicity of the genetically modified Mycoplasma pneumoniae bacterium is reduced as compared to a M129-B7 Мycoplasma pneumoniae bacterium; and wherein the reduction in pathogenicity and/or immunogenicity is characterized by a reduction of toxicity by at least 30% upon introduction into the host organism as compared to the M129-B7 Mycoplasmа рпеumоniae bacterium introduced into an otherwise identical host organism.
Claim 2. The genetically modified Mycoplasma bacterium of claim 1, wherein the bacterium further comprises a deletion, substitution, and/or insertion of one or more nucleotides in a gene or operon encoding a peroxide producing protein.
Grosshennig et al. disclose a genetically modified M. pneumoniae strain with a loss-of-function insertion in the virulence factor gene MPN133 (Table 1), which demonstrates reduced pathogenicity relative to the wild-type reference strain (Fig. 5).
Grosshennig et al. describes MPN133 as a lipoprotein required for the uptake of glycerol and being essential for the formation of hydrogen peroxide when the cells grow in the presence of glycerol. Moreover, MPN133 is essential for full cytotoxicity and was identified in previous studies as virulence factor. Grosshennig et al. shows that a M. pneumoniae mutant with a truncated MPN133 protein has reduced cytotoxicity compared to wild-type (Table 1, Fig. 5; page 897, col. 1 par. 2; pages 902-903, bridging paragraph).
Regarding claim 1, Grosshennig et al. describes MPN133 as a lipoprotein required for the uptake of glycerol and being essential for the formation of hydrogen peroxide when the cells grow in the presence of glycerol. Moreover, MPN133 is essential for full cytotoxicity and was identified in previous studies as virulence factor. Grosshennig et al. shows that a M. pneumoniae mutant with a truncated MPN133 protein has reduced cytotoxicity compared to wild-type (Table 1, Fig. 5; page 897, col. 1 par. 2; pages 902-903, bridging paragraph). The CARDS toxin is already well known in the art as a major virulence factor of M. pneumoniae, as already mentioned in Grosshennig et al. itself (page 896, col. 1, last 5 lines). Grosshennig et al. teach limitations of claim 6 MPN 162, MPN 284 (see table 1). Grosshennig et al. teach limitations of claim 32 (genes and operons of table 1) such as MPN043, MPN076, MPN077, MPN 133, MPN 134, MPN 162, MPN 284, MPN421, MPN 433, MPN 506 (see table 1). Grosshennig et al. teach limitations of claim 7 Mycoplasma pneumoniae M129 (see 897).
Grosshennig et al. do not teach MPN 372.
Baseman et al. describes methods of screening M. pneumoniae for mutants defective in the biological activity of the CARDS toxin, for use in a vaccine preparation, and teaches that CARDS toxin (MPN372) mutants of Mycoplasma pneumoniae (e.g., having a mutation in the CARDS coding sequence or lacking the CARDS coding sequence) can be generated through such art-known techniques as gene disruption see claim 1, ([0208] and [0209]). Baseman et al. teach MPN 372 (see para 0008, 0018, 0233, 0362, 00364, 0366, 0379, 0381, 0384). Baseman et al. teach limitations of claims vaccine 21 and 31 pharmaceutical composition (see para 0110, 0161, 0295). Baseman et al. teach limitations of claim 22 (see para 0008, 0080, 0096, 0208, 0261). Baseman et al. teach limitations of claims 23 and 24 exogenous antigenic and pathogenic sequences (see para 0072, 0152, 0157, 0261, 0310, 0331. 0374). Baseman et al. teach deletions, substitutions and insertions (see para 0096, 0097, 0124, 0153, 0154, 0157, 0392). Baseman et al. teach multiple nucleotides (see para 0031, 0032, 0039, 0048, 0052, 0057, 0062-0065). Baseman et al. teach limitations of claim 4, Mycoplasma pneumoniae and Mycoplasma penetrans (see para 0054-0056, 0064-0065, 0114, 0167, 0169, 0185-0189, 0193). Baseman et al. teach limitations of claim 7 Mycoplasma pneumoniae M129 (see para 0211-0212, 0378-0379, 0383).
Additionally, Waites et al. describes the CARDS toxin as a Mycoplasma-specific molecule and significant virulence factor of M. pneumoniae. According to Waites et al., transcription of the CARDS toxin-encoding gene (MPN372) is induced and protein levels increase upon exposure of M. pneumoniae to host cells, supporting roles for this protein in host cell interactions. Administration of purified recombinant CARDS toxin to model animals reproduces substantial features of M. pneumoniae disease. Positive correlation between CARDS toxin production and severity of disease among M. pneumoniae strains in an animal model reinforces the significance of this toxin as a disease determinant (page 755, last para and page 756 para 1).
MPN genes as well as information regarding their essentiality are generally available, e.g. from the MyMPN database, as reflected in page 791 of Waites et al.
Waites et al. teach limitations of claim 6 MPN 141, MPN 142 (page 777). Waites et al. teach limitations of claim 32 (genes and operons of table 1) such as MPN 13, MPN14, MPN15, MPN16, MPN49, MPN 133, MPN 140, MPN 141, MPN 142, MPN181, MPN 285, MPN 304, MPN 372, MPN 442, MPN459, MPN560, MPN560 (see pages 754,755, 757, 777).
It would have been obvious to one of ordinary skill in the art that to combine the teaching of above references to obtain a genetically modify bacterium. Because,
Grosshennig et al. disclose a genetically modified M. pneumoniae strain with a loss-of-function insertion in the virulence factor gene MPN133 (Table 1), which demonstrates reduced pathogenicity relative to the wild-type reference strain (Fig. 5). And Baseman et al. describes methods of screening M. pneumoniae for mutants defective in the biological activity of the CARDS toxin, for use in a vaccine preparation, and teaches that CARDS toxin (MPN372) mutants of Mycoplasma pneumoniae (e.g., having a mutation in the CARDS coding sequence or lacking the CARDS coding sequence) can be generated through such art-known techniques as gene disruption see claim 1, ([0208] and [0209]). The benefit of combining the above references is that all the refences teach genetically modified Mycoplasma and genes and operon. In view of teachings of Waites et al. a skilled person trying to further attenuate the strain of Grosshennig et al. would be motivated to target the CARDS toxin (MPN 372) as a major virulence factor and would do with a reasonable expectation of success.
Since the office does not have the facilities for examining and comparing applicants’
Mycoplasma pneumoniae with the Mycoplasma pneumoniae of the prior art, the burden is on the applicant to show a novel or unobvious difference between the claimed modified organism and the modified organism of the prior art (i. e., that
the Mycoplasma pneumoniae of prior art does not possess the same material structure and functional characteristics of the claimed Mycoplasma pneumoniae). See In re Best, 562 F.2 d 1252, 195 USPQ 430 (CCPA 1977) and In re Fitzgerald et al., 205 USPQ 594.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses combining prior art elements according to known methods to yield predictable results, thus the combination is obvious unless its application is beyond that person's skill. KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007) also discloses, "The combination of familiar element according to known methods is likely to be obvious when it does no more than yield predictable results". It is well known to combine different genes in a genetically modify organism, which function in a predictable manner to yield a reasonable expectation of success along with predictable results to one of ordinary skill in the art at the time of the invention. Thus, it would have been obvious to a person of ordinary skill in the art to combine prior art elements according to known methods that is ready for improvement to yield predictable results. The claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Applicants Arguments
14. Applicant's arguments filed 10/16/2025 have been fully considered but they are not persuasive. Applicants argue:
Applicant's claim 1 has been amended to recite that "the genetically modified Mycoplasma pneumoniae bacterium propagates in the lungs of a host organism." (emphasis added). Basis for the amendment to claim 1 can be found throughout the Specification and more specifically at page 41, line 35, through page 42, line 2, of the clean substitute specification filed herewith. The recitation of "propagates in the lungs of a host organism" indicates that the genetically modified Mycoplasma pneumoniae bacterium is a live bacterium that is able to survive for a sufficient time to allow propagation in the lungs of a host organism, while being further characterized by a reduced pathogenicity and/or immunogenicity when compared to Ml29-B7 Mycoplasma pneumoniae bacterium.
None of the cited references, alone or in combination, teach or suggest that such an attenuated yet live Mycoplasma pneumoniae bacterium can be obtained by removing or inactivating MPN133 and MPN372. The Office alleges that Grosshennig teaches that a Mycoplasma pneumoniae bacterium mutant with a truncated MPN133 protein has reduced cytotoxicity as compared to a wild type Mycoplasma pneumoniae bacterium. However, Grosshennig also teaches that Mycoplasma pneumoniae bacterium is highly dependent on uptake of glycerol and glycerophosphodiesters for nutrition and that MPN133 is essential for glycerol uptake (abstract):
The cited references do not teach or suggest elements recited in Applicant's claim 1, including that the genetically modified Mycoplasma pneumoniae bacterium propagates in the lungs of a host organism. (emphasis added). Claim 1 would therefore not be obvious in view of the cited references.
Even with the addition of Baseman and Waites, the references alone and/or in combination are missing elements recited in the claims
The addition of Baseman does not overcome the lack of elements in the combination, as the addition of Baseman and other cited references to Grosshennig, the combination does not teach or suggest elements recited in Applicant's claim 1. Baseman does not consider living genetically modified Mycoplasma pneumoniae bacteria but is limited to Mycoplasma pneumoniae proteins and biologically active fragments thereof. While Baseman refers to CARDS toxin (i.e., MPN372), Baseman does not teach that a Mycoplasma pneumoniae bacterium with an inactivated MPN372 would be viable and have the favorable properties as recited in the pending claims. Indeed, Baseman is exclusively directed to using certain genes such as the CARDS toxin but does not teach the use of genetically modified Mycoplasma pneumoniae bacteria.
The addition of Waites also does not add the elements missing in the combination. Waites is a review article wherein the CARDS toxin-encoding gene (MPN372) is discussed as a Mycoplasma pneumoniae exotoxin. On page 755, MPN372 is discussed as a significant virulence factor of Mycoplasma pneumoniae, the expression of MPN372 being correlated to the clinical manifestation of a Mycoplasma pneumoniae infection. Reference is made to MPN372 at distinct additional instances throughout Waites, each being in a context of diagnosing an infection and/or genotyping. At no instance in Waites is any teaching or suggestion made that MPN372 may be mutagenized or inactivated to arrive at a non-pathogenic yet viable Mycoplasma pneumoniae variant, let alone that such a mutagenized Mycoplasma pneumoniae variant would still retain in vivo replication capacity. This is particularly relevant in view of the above observations regarding the contents of Grosshennig that refers to a substantial amount of "moonlighting proteins" present in the Mycoplasma pneumoniae genome(s).
No reasonable expectation of success
While Grosshennig teaches that MPN133 is a virulence factor, a person or ordinary skill in the art at the time of the filing of the present application would not have been motivated to inactivate MPN133 in combination with MPN372, as it would be understood that this would come at a great fitness cost for the Mycoplasma pneumoniae when introduced into lungs of a host organism. Related hereto, Applicants wish to point out that Figure 5 of Grosshennig only evaluates cytotoxicity by measurement on HeLa cells. Such measurement does not account for the fitness cost that an MPN133 inactivation would entail. Hence, the reduced cytotoxicity in Figure 5 is actually the combination of the reduction in actual cytotoxicity and reduced fitness of the infecting Mycoplasma pneumoniae bacteria.
Neither Grosshennig nor any of the other cited prior art documents teach that MPN133 can be inactivated without a fitness cost of the bacterium. A person of ordinary skill in the art at the time of the present application would therefore not have inactivated MPN133 when searching for a Mycoplasma pneumoniae bacterium that is still capable of propagating in the lungs of a host organism, and which has a reduced toxicity. As Mycoplasma pneumonia comprises several genes that have been classified as virulence factors, the skilled person would have been motivated inactivate a different virulence factor as mutating MPN133 would have been understood to decrease the survival of the bacterium in the lungs of the host organism.
Moreover, even the notion that a skilled person would search for alternative genes altogether is highly doubtful. It should be appreciated that a relatively high amount of proteins expressed by Mycoplasma pneumoniae act as so-called "moonlighting proteins" (Grosshennig, page 903, left column). A skilled person would not blithely assume that proliferation in optimized medium equals the capacity to proliferate in a respiratory tract. This in itself is essentially an implicit warning to any person aiming to rationally mutagenize Mycoplasma pneumoniae bacteria.
In addition, no teaching can be derived on the in vivo replicative capacity of a MPN133 MPN372 double knockout Mycoplasma pneumoniae bacterium in Grosshennig, which is nonetheless demonstrated in detail by the Examples of the present application.
Combining the cited references would have no reasonable expectation of success of producing a genetically modified Mycoplasma pneumoniae bacterium that propagates in the lungs of a host organism. Claim 1 would therefore not be obvious in view of the cited references.
Office Response
15. Applicant's arguments filed 10/16/2025 have been fully considered but they are not persuasive.
In response to applicant's arguments that following added limitations has overcome the rejection such as, wherein the genetically modified Mycoplasma pneumoniae bacterium propagates in the lungs of a host organism; wherein the pathogenicity and/or immunogenicity of the genetically modified Mycoplasma pneumoniae bacterium is reduced as compared to a M129-B7 Mycoplasma pneumoniae bacterium; wherein the reduction in pathogenicity and/or immunogenicity is characterized by a reduction of toxicity by at least 30% upon introduction into the host organism as compared to the M129-B7 Mycoplasma рпеumоniae bacterium introduced into an otherwise identical host organism.
In response, Grosshennig et al. shows that a M. pneumoniae mutant with a truncated MPN133 protein has reduced cytotoxicity compared to wild-type (Table 1, Fig. 5; page 897, col. 1 par. 2; pages 902-903, bridging paragraph).
As to limitations that modified Mycoplasma pneumoniae bacterium propagates in the lungs of a host organism, this feature is an inherent property of the bacterium.
In response to applicant's arguments against the references individually, one cannot show non-obviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In response to applicant’s argument that none of the cited references, alone or in combination, teach or suggest that such an attenuated yet live Mycoplasma pneumoniae bacterium can be obtained by removing or inactivating MPN133 and MPN372. It would have been obvious to one of ordinary skill in the art that to combine the teaching of above references to obtain a genetically modify bacterium. Because, Grosshennig et al. disclose a genetically modified M. pneumoniae strain with a loss-of-function insertion in the virulence factor gene MPN133 (Table 1), which demonstrates reduced pathogenicity relative to the wild-type reference strain (Fig. 5). And Baseman et al. describes methods of screening M. pneumoniae for mutants defective in the biological activity of the CARDS toxin, for use in a vaccine preparation, and teaches that CARDS toxin (MPN372) mutants of Mycoplasma pneumoniae (e.g., having a mutation in the CARDS coding sequence or lacking the CARDS coding sequence) can be generated through such art-known techniques as gene disruption see claim 1, ([0208] and [0209]). The benefit of combining the above references is that all the refences teach genetically modified Mycoplasma and genes and operon. In view of teachings of Waites et al. a skilled person trying to further attenuate the strain of Grosshennig et al. would be motivated to target the CARDS toxin (MPN 372) as a major virulence factor and would do with a reasonable expectation of success.
Since the office does not have the facilities for examining and comparing applicants’
Mycoplasma pneumoniae with the Mycoplasma pneumoniae of the prior art, the burden is on the applicant to show a novel or unobvious difference between the claimed modified organism and the modified organism of the prior art (i. e., that
the Mycoplasma pneumoniae of prior art does not possess the same material structure and functional characteristics of the claimed Mycoplasma pneumoniae). See In re Best, 562 F.2 d 1252, 195 USPQ 430 (CCPA 1977) and In re Fitzgerald et al., 205 USPQ 594.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, it would be prima facie obvious at the time the invention was made It would have been obvious to one of ordinary skill in the art that to combine the teaching of above references to obtain a genetically modify bacterium as mentioned above.
MPEP 2143.02 II states that
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Obviousness does not require absolute predictability, however, at least some degree of predictability is required. Evidence showing there was no reasonable expectation of success may support a conclusion of non-obviousness. In re Rinehart, 531 F.2d 1048, 189 USPQ 143 (CCPA 1976) (Claims directed to a method for the commercial scale production of polyesters in the presence of a solvent at superatmospheric pressure were rejected as obvious over a reference which taught the claimed method at atmospheric pressure in view of a reference which taught the claimed process except for the presence of a solvent. The court reversed, finding there was no reasonable expectation that a process combining the prior art steps could be successfully scaled up in view of unchallenged evidence showing that the prior art processes individually could not be commercially scaled up successfully.). See also Amgen, Inc. v. Chugai Pharmaceutical Co., 927 F.2d 1200, 1207-08, 18 USPQ2d 1016, 1022-23 (Fed. Cir.), cert. denied, 502 U.S. 856 (1991) (In the context of a biotechnology case, testimony supported the conclusion that the references did not show that there was a reasonable expectation of success.); In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988) (The court held the claimed method would have been obvious over the prior art relied upon because one reference contained a detailed enabling methodology, a suggestion to modify the prior art to produce the claimed invention, and evidence suggesting the modification would be successful.). In this case,
Therefore, applicants arguments drawn to the modification taught in the prior art are found persuasive.
Claim Rejections - 35 USC § 103 Maintained
16. Rejection of claims 1-3,6 and 33-34 under 35 U.S.C. 103 as being unpatentable over Grosshennig et al. in view of Baseman et al. and Waites et al. and further in view of Hames et al., and Eduardo et al. is maintained.
The rejection was as stated below:
Claims 1-3,6 and 33-34 are rejected under 35 U.S.C. 103 as being unpatentable over Grosshennig et al. (Infection and Immunity vol.81, no.3, pp.896-904, 2013) in view of Baseman et al. (US20090104185 A1) and Waites et al. (Clinical Microbiology Reviews, vol. 30, no. 3, pp. 747-809, 2017) and further in view of Hames et al. (Journal of Bacteriology vol. 191, no.3, pp. 747-753, 2008) and Eduardo et al. (Journal of Biological Chemistry vol. 286, no.41 pp, 35367-35379, 2011).
All art of record applicants’ search report.
Claims are drawn to:
Claim 33. The genetically modified Mycoplasma pneumoniae bacterium of claim 2, wherein the gene or operon encoding a peroxidase producing protein is a gene or operon encoding glycerol-3-phospate dehydrogenase (MPN051).
Claim 34. The genetically modified Mycoplasma pneumoniae bacterium of claim 3, wherein the one or more genes or operons encoding a protein capable of eliciting Guillain-Barre in a host organism is one or more genes or operons encoding a UDP-glucose 4-epimerase (MPN257), and/or a glycosyltransferase (MPN483).
The teachings of Grosshennig et al, Baseman et al. and Waites et al. in regard to claims 1-3 have been mentioned above. The above references do not teach limitation of claim 33 (MPN051) and claim 34 (MPN483).
Hames et al. teach MPN051 is a well-known cytotoxic M. pneumoniae gene and teach MPN051 (glpD) mutants with reduced cytotoxicity (see abstract; Fig. 7; page 752, col. 1, par. 1+2). Hames et al. teach in contrast to the wild-type strain, the glpD mutant produced nearly no hydrogen peroxide under these conditions. Hames et al. teach Mycoplasma M-129 and insertion mutants (see material and methods).
Eduardo et al. teach that MPN483 is also known as homologue of MG517 glycosyltransferase, which upon inhibition results in Mycoplasma growth inhibition and is a potential therapeutic target against Mycoplasma infections see (abstract; Table 1; page 35376, col.2, last paragraph). Eduardo et al. recite that MG5l 7 is homologous to the M. pneurnoniae enzyme encoded by mpn483 gene, reported to produce similar glycolipid. Eduardo et al. teach limitations of claim 4 M. genitalium and M. pneumoniae and limitation of claim 6 MPN183 (see table 1).
Since the office does not have the facilities for examining and comparing applicants’ Mycoplasma pneumoniae with the Mycoplasma pneumoniae of the prior art, the burden is on the applicant to show a novel or unobvious difference between the claimed modified organism and the modified organism of the prior art (i. e., that
the Mycoplasma pneumoniae of prior art does not possess the same material structure and functional characteristics of the claimed Mycoplasma pneumoniae). See In re Best, 562 F.2 d 1252, 195 USPQ 430 (CCPA 1977) and In re Fitzgerald et al., 205 USPQ 594.
It would have been obvious to one of ordinary skill in the art that to combine the teaching of above references to obtain a genetically modify bacterium. Because,
Grosshennig et al. disclose a genetically modified M. pneumoniae strain with a loss-of-function insertion in the virulence factor gene MPN133 (Table 1), which demonstrates reduced pathogenicity relative to the wild-type reference strain (Fig. 5). And Baseman et al. describes methods of screening M. pneumoniae for mutants defective in the biological activity of the CARDS toxin, for use in a vaccine preparation, and teaches that CARDS toxin (MPN372) mutants of Mycoplasma pneumoniae (e.g., having a mutation in the CARDS coding sequence or lacking the CARDS coding sequence) can be generated through such art-known techniques as gene disruption see claim 1, ([0208] and [0209]). The benefit of combining the above references is that all the refences teach genetically modified Mycoplasma and genes and operon. In view of teachings of Waites et al., Hames et al. and Eduardo et al. a skilled person trying to further attenuate the strain of Grosshennig et al. would be motivated to target more genes and operon encoding MPN051 and MPN483.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses combining prior art elements according to known methods to yield predictable results, thus the combination is obvious unless its application is beyond that person's skill. KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007) also discloses, "The combination of familiar element according to known methods is likely to be obvious when it does no more than yield predictable results". It is well known to combine different genes in a genetically modify organism, which function in a predictable manner to yield a reasonable expectation of success along with predictable results to one of ordinary skill in the art at the time of the invention. Thus, it would have been obvious to a person of ordinary skill in the art to combine prior art elements according to known methods that is ready for improvement to yield predictable results. The claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Applicants; Arguments
17. Applicant's arguments filed 10/16/2025 have been fully considered but they are not persuasive. Applicants argue:
The Applicants note that other cited prior art documents are cited (i.e., Hames and Eduardo) as being relevant for certain dependent claims, such as for dependent claims reciting MPN05 l (Hames) and MPN483 (Eduardo). The Applicants note that none of these genes are recited in amended claim 1 presented herewith and therefore the Applicants wish to submit that these documents do not render the subject matter of claim 1 obvious.
The cited references are missing elements recited in Applicant's claim 1. Claim 1 would therefore not be obvious in view of the cited references. Therefore the § 103 rejection of claim 1 is overcome and should be withdrawn. Claims 2-3, 31 and 34 depend from claim 1 and likewise would not be obvious for the same reasons. Therefore, the§ 103 rejection of claims 2-3, 31, and 34 is overcome and should be withdrawn.
Office Response
18. Applicant's arguments filed 10/16/2025 have been fully considered but they are not persuasive.
In response to applicant's arguments against the references individually, one cannot show non-obviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In response to applicant's arguments that following added limitations has overcome the rejection such as, wherein the genetically modified Mycoplasma pneumoniae bacterium propagates in the lungs of a host organism; wherein the pathogenicity and/or immunogenicity of the genetically modified Mycoplasma pneumoniae bacterium is reduced as compared to a M129-B7 Mycoplasma pneumoniae bacterium; wherein the reduction in pathogenicity and/or immunogenicity is characterized by a reduction of toxicity by at least 30% upon introduction into the host organism as compared to the M129-B7 Mycoplasma рпеumоniae bacterium introduced into an otherwise identical host organism.
In response to Grosshennig et al. shows that a M. pneumoniae mutant with a truncated MPN133 protein has reduced cytotoxicity compared to wild-type (Table 1, Fig. 5; page 897, col. 1 par. 2; pages 902-903, bridging paragraph).
As to limitations that modified Mycoplasma pneumoniae bacterium propagates in the lungs of a host organism, this feature is an inherent property of the bacterium.
In response to applicant’s argument that none of the cited references, alone or in combination, teach or suggest that such an attenuated yet live Mycoplasma pneumoniae bacterium can be obtained by removing or inactivating MPN133 and MPN372. It would have been obvious to one of ordinary skill in the art that to combine the teaching of above references to obtain a genetically modify bacterium. Because, Grosshennig et al. disclose a genetically modified M. pneumoniae strain with a loss-of-function insertion in the virulence factor gene MPN133 (Table 1), which demonstrates reduced pathogenicity relative to the wild-type reference strain (Fig. 5). And Baseman et al. describes methods of screening M. pneumoniae for mutants defective in the biological activity of the CARDS toxin, for use in a vaccine preparation, and teaches that CARDS toxin (MPN372) mutants of Mycoplasma pneumoniae (e.g., having a mutation in the CARDS coding sequence or lacking the CARDS coding sequence) can be generated through such art-known techniques as gene disruption see claim 1, ([0208] and [0209]). The benefit of combining the above references is that all the refences teach genetically modified Mycoplasma and genes and operon. In view of teachings of Waites et al., Hames et al. and Eduardo et al. a skilled person trying to further attenuate the strain of Grosshennig et al. would be motivated to target more genes and operon encoding MPN051 and MPN483.
Since the office does not have the facilities for examining and comparing applicants’
Mycoplasma pneumoniae with the Mycoplasma pneumoniae of the prior art, the burden is on the applicant to show a novel or unobvious difference between the claimed modified organism and the modified organism of the prior art (i. e., that
the Mycoplasma pneumoniae of prior art does not possess the same material structure and functional characteristics of the claimed Mycoplasma pneumoniae). See In re Best, 562 F.2 d 1252, 195 USPQ 430 (CCPA 1977) and In re Fitzgerald et al., 205 USPQ 594.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, it would be prima facie obvious at the time the invention was made It would have been obvious to one of ordinary skill in the art that to combine the teaching of above references to obtain a genetically modify bacterium as mentioned above.
MPEP 2143.02 II states that
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Obviousness does not require absolute predictability, however, at least some degree of predictability is required. Evidence showing there was no reasonable expectation of success may support a conclusion of non-obviousness. In re Rinehart, 531 F.2d 1048, 189 USPQ 143 (CCPA 1976) (Claims directed to a method for the commercial scale production of polyesters in the presence of a solvent at superatmospheric pressure were rejected as obvious over a reference which taught the claimed method at atmospheric pressure in view of a reference which taught the claimed process except for the presence of a solvent. The court reversed, finding there was no reasonable expectation that a process combining the prior art steps could be successfully scaled up in view of unchallenged evidence showing that the prior art processes individually could not be commercially scaled up successfully.). See also Amgen, Inc. v. Chugai Pharmaceutical Co., 927 F.2d 1200, 1207-08, 18 USPQ2d 1016, 1022-23 (Fed. Cir.), cert. denied, 502 U.S. 856 (1991) (In the context of a biotechnology case, testimony supported the conclusion that the references did not show that there was a reasonable expectation of success.); In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988) (The court held the claimed method would have been obvious over the prior art relied upon because one reference contained a detailed enabling methodology, a suggestion to modify the prior art to produce the claimed invention, and evidence suggesting the modification would be successful.). In this case,
Therefore, applicants’ arguments drawn to the modification taught in the prior art are found persuasive.
Conclusion
19. No claims are allowed.
20. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KHATOL S SHAHNAN SHAH whose telephone number is (571)272-0863. The examiner can normally be reached on Mon-Tue, Thurs-Fri 12pm-8pm.
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/KHATOL S SHAHNAN SHAH/Examiner, Art Unit 1645 January 28, 2026
/JANA A HINES/Primary Examiner, Art Unit 1645